[Frontiers in Bioscience 16, 187-207, January 1, 2011]
Telomere protein complexes and interactions with telomerase in telomere maintenance
Alexander Ruvantha Pinto 1, He Li1, Craig Nicholls1, Jun-Ping Liu 1
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TABLE OF CONTENTS
1. ABSTRACT
Telomeres are the termini of linear chromosomes. They are composed of DNA and DNA-binding proteins critical for maintaining chromosome integrity and cellular function. Telomere binding proteins regulate the structure and function of telomeres through the formation of different complexes with telomeric DNA. Double- and single-stranded telomeric DNA binding protein complexes have shared and unique functions that regulate telomere homeostasis. Recent studies have shown that telomerase interacts with several telomere-binding protein complexes including shelterin, CST, DNA-dependent protein kinase (DNA-PK) and MRN. The present review describes the recognised telomere-binding protein complexes, sub-complex exchanges and inter-complex molecular interactions. It also discusses the evidence suggesting that telomerase reverse transcriptase (TERT) switches between different complexes. Studies of the telomere protein inter-complex interactions and the switching of components between complexes provide insight into their fundamental roles of programming telomere length and configuration, and thus cell proliferative potential.
Telomeres, the termini of linear chromosomes, serve the primary function of providing integrity at each chromosomal end in resting and mitotic cells (1-3). This consequently confers both chromosomal stability and a regulatory mechanism during cell division (4). Telomeres achieve their function through interacting with many telomere binding proteins and components of the DNA repair machinery (2). Thus, telomeres prevent undesirable DNA damage and repair activities, and permit spatial-temporal regulation of chromosome ends in a cell cycle dependent manner. Different telomere configurations mediate chromosomal segregation and nuclear organisation and different telomere lengths determine cellular proliferative potential. The loss of telomeric DNA, or associated protein substructures, leads to chromosome instability and inter-chromosomal fusions, culminating in cell death or neoplastic development.
The fundamental roles of telomeres depend on intact telomeric structures that both incorporate and are regulated by telomere binding proteins (5). Telomere binding proteins coat telomeres in layers regulating telomere configuration and length. In turn, the configuration and number of telomeric repeats influence telomere protein complex formation. The telomere protein complexes form, interact, and disintegrate in response to cellular states such as cell proliferation, differentiation, senescence and immortalisation. Despite the growing body of data, the understanding of telomere-protein interactions is rudimentary.
Recent reviews have covered in detail telomere binding proteins in yeast and humans (5-6), the regulation of telomere lengthening and stabilisation (7), telomeres dynamics in cancer (8-9), alternative lengthening of telomeres (10), the shelterin/telosome complex (11-12) and recruitment mechanisms of telomerase (13-14). Here, we focus on the major telomere protein complexes, including telomere complex interactions, sub-complex switching, and, in particular, the interactions of telomerase with other telomere-binding complexes in mammalian cells.
3. Telomere shortening and lengthening
Human telomeric DNA is comprised of a tandemly repeating sequence of TTAGGG that in humans extends 7-15 kb (1, 15). The G-rich strand of telomeric DNA extends in the 3' direction to form a single-stranded overhang of approximately 150 nucleotides (16-17). The overhang is able to form a lasso-like structure - the telomere loop or 'T-loop' (18-19) - which is thought to serve a protective function (Fig. 1). The T-loop is formed when the 3'-overhang invades the telomere duplex and binds to its complementary sequence. The point at which the 3'-overhang resects duplex DNA and inserts itself is termed the 'D-loop' (displacement loop). Formation of the T-loop is partly dependent on the size of the 3' overhang. The telomere erosion associated with loss of 3'overhang lessens the ability to form the T-loop and results in loss of telomere end protection (20).
Telomere shortening accompanies normal somatic cell division due to the 'end replication problem' (21-24) that arises from the use of Okazaki fragments to prime DNA synthesis. On linear chromosomes, the last Okazaki fragment that primes synthesis of the lagging-strand will leave a gap that cannot be filled, leading to incomplete replication of the chromosome (25-26). Hence, human and mouse telomeres shorten at rates between 50 and 150 bp per cell division (27-28). Erosion of telomeres beyond a critical threshold induces permanent exit of the cell cycle. This phenomenon is known as replicative senescence and the number of divisions required to reach it is termed the 'Hayflick limit'. This process was first observed in experiments on fibroblasts, which were shown to have a finite proliferative capacity (29). In humans, telomere shortening is thought to serve as a 'mitotic clock' protecting against inappropriate cellular proliferation that can lead to cancer cell formation. Telomere shortening is also the basis for the 'telomere hypothesis' of ageing (23). Therefore, prolonged proliferation of some cells requires a means of telomere maintenance to stabilise telomere length and prevent the onset of replicative senescence.
To overcome the end-replication problem, highly proliferative cells such as germ line or stem cells express the ribonucleoprotein complex telomerase (30-32). Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPS cells) express high levels of telomerase (33-34). However, progressive differentiation is associated with a decrease in telomerase expression and the activity (35-38). Therefore, high levels of telomerase and long telomeres are observed in ESCs, and low levels of telomerase and shorter telomeres are observed in more differentiated cells. Differentiation-induced telomerase repression occurs through multiple pathways, including chromatin modification of the genes encoding the various components of telomerase (38). Therefore, most human adult somatic cells either lack telomerase activity completely or have levels insufficient to overcome the Hayflick limit (39). The importance of telomerase in prolonged proliferation has been demonstrated by ectopic over-expression of the telomerase catalytic subunit (TERT), which enables somatic telomerase-negative cells to overcome the Hayflick limit (40-42). In comparison, most cancer cells express high levels of telomerase (42). The presence of telomerase activity in approximately 90% of human malignancies (43) and the finding that inhibition of telomerase in cancer cells induces cell senescence and eventually cell death (44) suggest that telomerase could aid in the diagnosis of cancer and provide a potential target for cancer therapies (45).
Telomeres can also be extended by the mechanism termed 'alternative lengthening of telomeres' (ALT) that is independent of telomerase. The ALT mechanism involves replication of telomeric DNA by homologous recombination. Although the precise mechanism of recombination in ALT is not known, current theories include a roll-spread replication mechanism that incorporates the use of circular telomeric DNA, elongation of a telomere end using a sister telomere as a template, and elongation of the 3' end of the telomere within the T-loop configuration (46-48).
4. Telomere binding protein complexes
The nature of the specialised nucleoprotein cap (49-50) that protects the tips of telomeric DNA is not fully understood, however, several telomere binding proteins and complexes have been identified, some of which are unique to telomeres. Changes to the composition of telomere binding proteins, by silencing or over-expression of individual or multiple proteins, alter telomere homeostasis in a way that usually manifests as telomere shortening, lengthening or fusion. The shelterin and Rap-TRF2 complexes are two large telomere-specific multi-protein complexes that were identified in mammalian cells by mass spectrometry (51-53). Both complexes have interchangeable protein components and gain access to double-stranded telomeric DNA by binding either TRF1 or TRF2. The POT1-TPP1 and CST complexes, like telomerase, are single-stranded telomere binding protein complexes.
The telomerase complex, with a molecular mass between 650 and 670 kD (54), is a specialised reverse transcriptase comprised of a catalytic core and several associated proteins. The catalytic core of human telomerase contains the catalytic subunit TERT, a 1132-amino acid residue reverse transcriptase; the 451-nt RNA moiety TER; and the TER binding protein dyskerin, a 514-amino acid residue protein (54). In addition to the catalytic core, the telomerase complex includes several other telomerase binding proteins, such as the ATPases pontin and reptin (55), the TER binding proteins Garl1, Nop10 and NHP2 (56), telomerase Cajal body protein 1 (TCAB1) (57), and heat shock proteins hsp90 and p23 (58-59). Although TER and dyskerin are expressed ubiquitously in normal and cancer cells (60-65), TERT is specifically present in highly proliferative or cancerous cells (65-67) and subject to positive and negative regulation by opposing cellular factors (reviewed in (68)).
TER and TERT are both regulated by alternative splicing which may alter telomerase-telomere complexes. TER exists in multiple forms including the short mature functional form and the immature longer TER RNA precursor that contains multiple polyadenylation sites and poly (A) tails of variable length (69). The findings in budding yeast that inhibition of TER splicing generates inactive forms of telomerase and causes progressive telomere shortening suggest that TER splicing is an important regulatory step in the biogenesis of functional yeast telomerase (69). Various forms of TERT arise from alternative splicing of TERT mRNA (70). Such telomerase complexes may exist in different forms with or without altered levels of telomerase activity. Ectopic expression of wild type TERT in telomerase-negative cells is sufficient to generate telomerase activity and extend cell lifespan, demonstrating that TERT is the rate-limiting component of telomerase (41). Therefore, the fate of telomerase largely depends on the presence and/or biological activity of both TER and TERT. Many strategies to regulate telomerase, such as in cancer therapies, target the expression or activity of TERT or TER.
To initiate reverse transcription, telomerase recognises, binds and orientates the 3'-overhang of telomeric DNA into its active site. TERT then copies the TER template one nucleotide at a time, until it reaches the 5′-boundary of the template region (71), where TERT undergoes a translocation to the newly formed telomere 3'-end for reverse transcription of another telomeric DNA repeat. TERT contains DNA-binding regions known as anchor sites upstream of the RNA-DNA hybrid to stabilise TERT binding to telomere (71). The actions of telomerase in stabilising and elongating telomeres are regulated by other telomere binding protein complexes, including shelterin (see below). Telomerase assembly and stabilisation, recruitment to telomeres, and reverse transcription activity and processivity at telomeres are regulated by telomere binding proteins.
The RNA moieties at telomeres are also implicated in regulating telomerase holoenzyme assembly and activity. These include TER and TER-binding protein complexes that facilitate telomerase complex formation and telomeric repeat-containing RNA (TERRA). TERRA is transcribed from the C-rich strand of sub-telomeric DNA by DNA-dependent RNA polymerase II (72-73) and is localised to telomeres. It inhibits telomerase activity, perhaps by mimicking the substrate nucleotide sequence of TER and thereby competing with TER interaction with its substrate (73). Consistent with the telomerase inhibitory function of TERRA, reduced levels have been associated with increased cytosine methylation in the sub-telomere region of telomerase-positive cells, suggesting that methylation silences TERRA transcription to allow telomerase-mediated maintenance of telomeres (74).
Recently, studies have demonstrated that telomerase holoenzyme assembly is dependent on the AAA+ family ATPases pontin and reptin that shuttle between TER and TERT to form two sub-complexes (55). Pontin and reptin are essential for the structural integrity and catalytic activity of several chromatin remodelling complexes. Pontin-reptin complex interacts with TERT during S-phase of the cell cycle, but is not required for telomerase activity, suggesting that the ATPases are primarily involved in telomerase assembly (55).
Since telomerase has been shown to exert its function in addition to telomere length maintenance (75-76), studies have been carried out to investigate possible interactions of TERT with proteins not associated with telomere maintenance (see below). In addition, effects observed following telomerase activation and inactivation may not result from changes in telomere length or stabilization, but also from the telomere position effect (TPE) impacting on gene expression (77). The telomere-independent effects of TERT might thus involve TERT forming a complex with other transcription regulatory molecules or TER interactions with proteins other than TERT (see below).
It has been demonstrated that telomerase cellular function can be independent of telomerase maintenance of telomeres (78). Expression of telomerase inhibits the anti-proliferative effect of TGF-β (79). Whereas inhibition of TERT increases the susceptibility of cells to apoptosis, expressing catalytically inactive TERT mutants enhances the survival of cells (80-82). Investigating the apparent telomere maintenance-independent function of TERT, recent studies have shown that TERT forms a complex with certain gene promoters, such as mouse and human beta-catenin (83). In human cancer and mouse ES cells, TERT forms a complex with BRG1 (Brahma-related gene 1 or called SMARCA4 (83). BRG1 is an ATPase subunit of the SWI/SNF chromatin remodeling enzymes that disrupt histone-DNA contacts), and activates Wnt-dependent reporters for beta-catenin gene transcription (83). The SWI/SNF (switch/sucrose non-fermentable) complex regulates gene expression by altering chromatin structures during epigenetic regulation (84). Interestingly, BRG1, complexed with p54nrb (a DBHS (Drosophila behaviour, human splicing) family protein), has already been shown to be involved in TERT gene transcription and splicing of the TERT transcript in human tumor cells (85). Thus, a positive regulation may exist for BRG1 to regulate not only the TERT gene but also TERT gene transcriptional action. BRG1-p54nrb complex up regulates TERT (85), and subsequently, BRG1-TERT up regulates beta-catenin (83).
The switching mechanisms in controlling BRG1 interactions with the TERT gene or TERT protein are unknown. In human HeLa cells, BRG1 co-purified with TERT, and in mouse ES cells, TERT binds BRG1 in both co-immunoprecipitation and GST fusion pull-down assays (83). The mechanism of TERT stimulating the beta-catenin gene transcription independently of telomeres was demonstrated by chromatin immunoprecipitation of the endogenous TERT with gene promoters of Wnt-dependent genes (83). Additional evidence for the direct participation of TERT in Wnt/beta-catenin signalling, through the role of TERT as a cofactor in a beta-catenin transcriptional complex, comes from studies showing TERT to be essential for both the formation of the anterior-posterior axis in Xenopus laevis embryos, and homeotic transformations in the vertebrae of Tert2/2 mice with Wnt signalling defects (83). However, recent studies have also shown that lack of either TERT or TER has no effect on differential gene expression in mice (86).
In addition, studies have shown that TERT is recruited to promyelocytic leukaemia (PML) nuclear bodies through its interaction with PML-IV (87). In the H1299 human lung carcinoma cell line, the binding is mediated by interactions between the PML-IV C-terminal region (residues 553-633) and two regions of TERT (residues 1-350 and 595-946) (87). The inhibition of telomerase activity by PML-IV occurs in HEK293T, U2OS and HTT cell lines, and is mimicked by the amino acid 553-633 fragment of PML-IV but not other PML isomers in H1299 cells (87). These findings are consistent with PML-induced premature senescence and up-regulation of p53 (88). Furthermore, treatment of H1299 cells with interferon-alpha (IFN-alpha) results in increased levels of PML proteins and a concurrent decrease in telomerase activity (89-90). IFN-alpha induces the localisation of exogenous TERT to PML nuclear bodies and increases the binding between TERT and PML, whereas depletion of PML reverses IFN-alpha-induced telomerase inhibition (87). These results suggest that PML-IV forms a complex with telomerase to regulate compartmentalisation and availability of TERT.
It is fundamental to address if TERT forms complexes with other protein(s) at telomeres, particularly with proteins that regulate or inhibit TERT telomere lengthening activity. Human Pif1 binds telomeres and also TERT (91-92). Consistent with yeast Pif1 that inhibits telomerase catalytic activity (93) and removes telomerase off the telomeres (94), human Pif1 inhibits telomerase processivity resulting in telomere shortening in fibrosarcoma HT1080 cells (92). Moreover, Pif1 inhibition of telomerase activity has been suggested to be mediated by Pif1 helicase activity in unwinding the DNA/RNA duplex formed by telomerase RNA TER and telomeric DNA (92), consistent with the removal activity of telomerase from telomeres in yeast (94). However, although Pif1 is detected in mouse embryonic and hematopoietic lineages, knockout of Pif1 in mice results in viable and apparently healthy animals without affecting telomere maintenance and telomerase activity (95).
Furthermore, the house-keeping glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) undergoes nuclear translocation in response to cellular stress (96-97) and binding to telomere (98-99). Studies in our laboratory found recently that GAPDH binds TERT and inhibits telomerase activity, suggesting a novel mechanism mediating stress-induced telomere shortening (unpublished data). Further studies are required to define the switching mechanisms of TERT in the different complexes of telomerase containing TER, the gene transcription co-factor complex containing BRG1, the TERT PML complex containing PML-IV, TERT-Pif1 and TERT-GAPDH complexes. Such switching requires regulation not only of TERT trafficking and interaction with different recruiting molecules, but also of the availability of TERT binding partners (such as BRG1, PML-IV and GAPDH).
Human TER is related to box H/ACA small ribonucleoprotein particles (RNPs) (100-102) of which there are at least two functional complexes. First, the box H/ACA small nucleolar (sno)RNPs that accumulate in the nucleolus and direct the modification of rRNAs and spliceosomal U6 snRNA; second, the box H/ACA small Cajal body-specific (sca)RNPs that accumulate within Cajal bodies and are involved in the modification of the nucleotides of spliceosomal snRNAs transcribed by RNA polymerase II (103-104). Human TER features at its 3′-end conserved H- and ACA-boxes involved in RNA splicing (105), and a CAB-box involved in the retention of scaRNPs within Cajal bodies (106) where TER accumulates in a cell cycle dependent manner (57, 102, 107-108). It appears that the integrity of the TER H-box or the ACA-box is required for normal biogenesis and accumulation of TER (100). Similar to other H/ACA RNAs, TER binds the four conserved proteins dyskerin, hGar1, hNhp2, and hNop10 to form the snoRNPs and scaRNPs (109-110). In addition, the interaction of TER with hNaf1 is required for telomerase assembly (111). It is not known how dyskerin, hGar1, hNhp2, hNop10 and hNaf1 are assembled with TER. However, silencing of TCAB1, a protein enriched in Cajal bodies that interacts TER and other scaRNAs, disrupts the association of TERC with Cajal bodies and telomere elongation by telomerase. This suggests that TCAB1 recruits TER to Cajal bodies playing a role in telomerase assembly and activity (57).
The shelterin complex, also known as the telosome, is a unique multi-protein telomere-specific interactome that maintains telomere structure and caps telomere ends (51, 112). The protein complex is made up of six proteins that bind both single- and double-stranded telomeric DNA to regulate telomere maintenance. They are TRF1, TRF2, POT1, TIN2, TPP1 and RAP1, which collectively contribute to normal telomere function. The core components of the shelterin complex are TRF1 and TRF2, which bind double-stranded telomeric DNA repeats in mammals. TRF1 and TRF2 form homodimers by an N-terminal homodimerization domain and bind strongly to duplex telomeric DNA through Myb-type DNA-binding domains called teloboxes (113-114). In doing so, TRF1 and TRF2 provide access points by which a range of proteins can interact with telomeres indirectly.
TRF1 is essential for telomere capping and regulation of telomere length and also serves as a critical factor in efficient replication of telomeric DNA (115). Whereas over expression of TRF1 results in telomere shortening (116-119), depletion of TRF1 results in rapid induction of the telomere damage response and cell senescence in an ATM/ATR-dependent manner (120). Over-expression of TRF1 in transgenic mice also results in increased telomere damage foci, end-to-end chromosomal fusions and telomere recombination (121). TRF1 binding is proportional to telomere length (118), and is believed to form a negative feed-back loop to restrict elongation of long telomeres by telomerase.
In contrast, TRF2 is critical for defining the ends of the chromosome as telomeres. Inhibition of TRF2 results in the detection of telomeres as DNA breaks, causing telomere fusions and eventually cell death or senescence (118, 122-123). TRF2 is believed to protect telomeres by aiding the formation of T-loops (18, 124) and direct suppression of DNA damage responses. It has been proposed that TRF2 interacts with Chk2, an ATM/ATR pathway effector kinase, to suppress its activation in the absence of DNA damage (125). In addition, TRF2 associates at telomeric and non-telomeric genomic double-strand breaks within 2 seconds following DNA damage insults, even in the absence of other key DNA-repair proteins (126).
POT1 and TPP1 each possess an oligonucleotide/oligosaccharide binding (OB) fold that facilitates single-stranded DNA binding (127-129). However, despite having an OB fold, TPP1 does not interact with telomeric DNA directly (128), whereas POT1 specifically binds TTAGGGTTA motifs (130-131). POT1 and TPP1 are involved in modulating telomerase activity (128, 132). Inhibition of both proteins by shRNA leads to telomere elongation (53). Inhibition of either POT1 or TPP1 alone leads to a potent DNA damage response at telomeres, caused by disruption of POT1-TPP1 complex at the telomere overhang (133-135).
To fulfil the functions of the single human POT1 gene, mice have two gene isoforms - POT1a and POT1b. Deletion of POT1a results in an increase in telomere length and ATR dependent DNA damage response (136-137). Deletion of POT1b results in large 3'overhangs (136) and an ageing phenotype that manifest as a dyskeratosis congenita-like syndrome including hyper-pigmentation and fatal bone marrow failure (138). These findings suggest that telomere capping by POT1 is critical for prevention of an ageing phenotype (134). However, more recent studies have shown that TPP1 is required for POT1a and POT1b binding to telomeres, since deletion of TPP1 in mouse embryo fibroblasts results in telomere dysfunction identical to that induced by double gene disruption of POT1a and POT1b (135).
TRF1-interacting nuclear protein 2 (TIN2) links the POT1-TPP1 heterodimer and the TRF1-TRF2 double-stranded DNA binding complexes (Fig. 1) (51, 139-140). The stable interaction also bridges TRF 1 and TRF2 homodimers that otherwise do not interact (51, 112, 140-141). Knockout of the mouse TIN2 gene results in early embryonic lethality highlighting its importance to telomere function (142). In addition, a significant number of human patients with dyskeratosis congenita have mutations in the TIN2 gene (143-144).
RAP1 (repressor activator protein 1) has been identified as a component of the shelterin complex that is also often mutated in human dyskeratosis congenita patients. Human RAP1 has a single Myb-homology domain, but appears not to bind telomeric DNA directly (145). RAP1 interacts with TRF2 to form a distinct complex (see below). Although the precise role of RAP1 is unknown, knockdown of RAP1 expression by shRNA results in telomere lengthening (52), suggesting that RAP1 is a negative regulator of telomere length maintenance.
Quantitative immunoblotting to determine the stoichiometry of shelterin proteins in the protein bound fraction of DNA has yielded clues to additional roles of shelterin components. Interestingly, the TPP1-POT1 heterodimer is in excess of its single-stranded telomeric DNA binding sites, suggesting that the complex might associate with non-telomeric DNA (146). Whereas TRF2 and Rap1 are present at 1:1 ratio, as are TPP1 and POT1, TIN2 is 10 fold less abundant than TPP1 and POT1. The discovery of more abundant RAP1 and TIN2 than previously thought indicates as yet unidentified roles of RAP1 and TIN2 in telomere maintenance or telomere-independent functions (12). In addition, sufficient TRF1 and TRF2 is present to allow binding of all telomeric DNA in cells with short telomeres and similar results were obtained for primary and transformed human cells, with short and long telomeres respectively, suggesting that there is no relation between protein proportions and telomere length (146).
Originally identified in yeast, the CST telomere binding protein complex caps telomeres and protects them from lethal DNA degradation. In yeast the complex is comprised of Cdc13 and the Stn1-Ten1 heterodimer that Cdc13 binds weakly (147-149) (Fig. 2). In humans (and other organisms), the CST complex contains conserved telomere maintenance component 1 (CTC1) and mammalian STN1 and TEN1 homologs (150-151). The CST proteins contain multiple putative OB-folds and the complex binds to single-stranded DNA with high affinity in a sequence-independent manner (150). Knockdown of CTC1 or STN triggers increased single-stranded G-strand overhangs and telomere loss (150-151). Structural studies suggest that the Stn1-Ten1 heterodimer is a conserved replication protein A (RPA)-like telomeric complex that may operate in parallel with the POT1-TPP1 dimer at 3' overhangs (152-153). Indeed, it was recently reported that OBFC1/AAF44, the human homolog of yeast Stn1, binds single-stranded telomeric DNA and associates with TPP1 to regulate telomere length (154). Mutation of OBFC1/AAF44 leads to telomere elongation in human cells, suggesting an important role in telomere length regulation (154).
RAP1 is part of another telomere binding complex that includes TRF2, Rad50, MRE11, Ku70, Ku80, and PARP1 (52) (Fig. 3). MRE11 and RAD50 are also components of the MRN complex that bind DNA, whereas Ku70 and Ku80 are components of the DNA-PK complex (see below). MRE11, RAD50 and Ku70/80 perform an important role in telomere homeostasis by capping telomeres and also regulating telomere maintenance. The poly(ADP)-ribosylase PARP1 binds and modifies TRF2, affecting its DNA binding (155-156). Similarly, other poly(ADP)-ribosylating enzymes, such as PARP2, and Tankyrases 1 and 2, are important for telomere integrity and maintenance (155, 157-160). However, the mechanisms by which these proteins contribute to telomere homeostasis are unclear. Silencing PARP1 results in telomere shortening without altering telomerase activity, and the release of cells from PARP1 inhibition leads to the rapid regeneration of telomeres (161).
The MRN complex, comprised of MRE11, RAD50 and NBS1, is required for maintenance of telomere length in mammals, plants and yeast (162). It is involved in all activities responsible for telomere integrity, including DNA repair, telomere capping and telomere lengthening. Although MRE11 and RAD50 bind DNA directly, NBS1 binds indirectly through MRE11, stabilising the interaction between MRN and DNA (163). The MRN complex may be involved in four functions: telomere capping, generation of the 3'-G rich overhangs, regulation of telomerase, and triggering telomeric DNA damage responses. The possible telomere capping role of MRN is supported by observations that NBS1-deficient cells have shorter telomeres (164) and cells expressing mutant NBS1 have unstable telomeres (165). Furthermore, NBS1 interacts with TRF2 during S-phase (166) and although the precise role of the MRN/TRF2 interaction is unclear, it may be related to T-loop formation.
The capping function of MRN is particularly important for protecting 3'overhangs after DNA synthesis in the G2 phase of the cell cycle (167). Gene silencing to reduce MRN results in a transient shortening of the 3' overhang in telomerase-positive cells (168). When telomeres are critically short, MRN is also involved in initiating telomeric DNA damage responses. MRE11 can directly activate ATM in response to DNA double-strand breaks (DSBs), triggering ATM-dependent DNA damage responses (169). MRN accumulates at damaged telomeres with 53BP1, γ-H2AX and phosphorylated ATM to form telomere dysfunction-induced foci (TIF) (140, 170-171). Recent data show that MRN contributes to telomere fusions arising from TRF2 deficiency in G1 phase of the cell cycle (167), and NBS1 is critical for activation of the ATM pathway in response to telomere dysfunction (167, 172). The nuclease activity of NBS1 is also important for the induction of telomere-chromosomal fusion (172). Consistently, MRN nuclease deficiency is required for MRN induction of ATM after DNA damage (173). Therefore, MRN is a multifaceted protein complex able to protect telomeres and elicit DNA damage response.
DNA-dependent protein kinase (DNA-PK) is composed of three subunits, Ku70, Ku80, and the catalytic component DNA-PKcs (DNA-dependent protein kinase catalytic subunit). With DNA ligase IV, Artemis and XRCC4, DNA-PK is a core component of the mammalian non-homologous end joining (NHEJ) machinery (174). DNA-PK interacts directly with telomeric DNA in yeast (175) and indirectly in mammals through interactions with TRF1 and TRF2 (176-177). In human cells, DNA-PK interacts with telomerase directly by binding TERT through Ku70 and Ku80 (178). DNA-PK is involved in telomere capping and telomerase regulation. Consistent with the telomere capping function of DNA-PK, Ku80-deficient mouse primary cells show increased telomere fusions and long telomeres (176, 179). In addition, Ku70 and TRF2 are required for repression of exchanges between sister telomeres (180). Therefore, DNA-PK contributes to telomere capping and prevents homologous recombination of telomeres.
4.7. Other telomere protein complexes
In addition to the multiprotein complexes described above, numerous other telomere binding proteins that are important for telomere maintenance and integrity have been identified in mammalian cells. These include Rad51D (181), Apollo (182-184), GNL3L (185), WRN and BLM helicases (186-190), and ERCC/XPF (191-193) (Table 1). Many of these proteins (Apollo, GNL3L, WRN, BLM and ERCC/XPF) interact with, and modulate the activities of TRF1 or TRF2. In addition, BLM in concert with TRF1 has been identified as necessary for efficient replication of TTAGGG-bearing telomeric DNA and prevention of replication fork stalling during S-phase (115). However, how these proteins interact with other telomere binding complexes, if they do at all, is yet to be fully understood.
5. InteractionS between telomerase and telomere binding complexes
Telomere binding proteins serve as gate keepers that regulate the access of telomerase to its substrate. They limit access either by direct cis-inhibition of telomerase at telomeres, or by modulating telomeric chromatin into configurations that deny telomerase access. It is thought that two telomeric configurations regulate the access of telomerase to telomeres. One is the 'open' configuration in which the D-loop is unlocked and the T-loop is open, presenting the 3'overhang for telomere elongation by telomerase. The second, 'closed' configuration involves an intact D-loop that conceals the 3'overhang, thereby limiting access of telomerase to telomeres. It is not known how the structure of telomeres switches between the open and closed configurations. Even in the "open" form, the 3' overhang may still be unavailable as a substrate for telomerase elongation due to the presence of single-stranded telomere binding protein complexes that conceal telomere termini and regulate telomerase recruitment through protein complex interactions.
5.1. Interactions between telomerase and shelterin complexes
Whereas TRF2 plays an important role in formation of the T-loop (124, 194-195), TRF1 is involved in cis-inhibition of telomerase. TRF1 over-expression leads to telomere shortening (118-119), and dominant negative TRF1 leads to telomere elongation (119), except in ALT cells, suggesting that TRF1 mutation-induced telomere lengthening depends on telomerase (117). Furthermore, direct tethering of TRF1 to the telomeres of specific chromosomes leads to shortening of those telomeres, confirming a cis inhibitory effect on telomere lengthening (116). Since TRF1 binding to telomeres is proportional to telomere length (118, 131), cis-inhibition of telomerase by TRF1 may have evolved to give shorter telomeres priority for elongation. TRF1 might achieve cis-inhibition by mechanisms that include the recruitment of proteins that inhibit telomerase directly or modify telomere conformation. Depletion or mutation of TRF1's shelterin partners, POT1, TIN2 and RAP1, results in lengthening of telomeres, implicating the shelterin complex in preventing access of telomerase to telomeres (52, 112, 132).
However, POT1 can have a dual role in regulating telomerase. Purified recombinant POT1 binds telomeric DNA and inhibits telomerase activity in vitro, possibly by sequestering the telomere ends (196). Conversely, POT1 enhances telomerase processivity by binding to telomeric DNA and presenting telomerase a single strand substrate of 8 nucleotides for telomere elongation (197). When POT1 associates with TPP1 on single-stranded telomeric DNA, the heterodimer protects telomeres by capping and elongates telomeres by recruiting telomerase (128-129) (Fig. 3). POT1 binds telomeric DNA with increased affinity and enhances telomerase processivity when bound to TPP1, which directly interacts with TERT in vitro in a TPP1 OB-fold dependent manner (128-129). Thus, the regulation of telomerase activity by POT1 depends on interactions with other proteins on double- and single-stranded telomeric DNA.
These observations demonstrate the critical role of TPP1 in recruiting telomerase to telomeres in a POT1 dependent manner (129). A hypomorphic mutation in the mouse TPP1 alleles is associated with telomere capping defects leading to adrenal gland dysplasia, male germ cell loss and skin hyperpigmentation (198). Moreover, mice lacking both p53 and TPP1 function are predisposed to rapid development of cancer and a shift from sarcomas and lymphomas to dominant carcinomas (including skin carcinoma and adrenocortical carcinoma) (198). The similarity in phenotype of mice with double deficiencies in TPP1 and p53, and telomerase TERC and p53 (199), is consistent with the TPP1/POT1 function in recruiting telomerase to telomeres.
POT1 has also been shown to interact with the nuclear protein PINX1, which may regulate the recruitment of telomerase onto telomeres by TPP1/POT1 (200). PINX1 binds both TERT and telomeric DNA and inhibits telomerase activity directly (201). Genetic ablation of PINX1 expression in yeast cells results in shortened telomeres (202). Knock down of constitutive PINX1 expression in telomerase-positive human cancer cells in vitro and xenograft tumours in mice also leads to telomere shortening and growth inhibition, apparently due to decreased association of telomerase with the POT1-containing telomeric protein complex (200). Therefore, PINX1 is required for telomerase recruitment and telomere maintenance in telomerase-positive cancer cells.
5.2. Interactions between telomerase and CST complexes
In budding yeast, Cdc13 binds either Stn1-Ten1 or Est1 (telomerase), in order to form operative complexes that caps or extends single-stranded G-rich telomeric DNA (203). The C-terminal region of Cdc13 mediates the Stn1-Ten1 interaction and the N-terminal region mediates the telomerase interaction with telomeres (204). The telomere capping and extending activities of Cdc13 are modulated by the yeast Hsp90 chaperone Hsp82, which promotes the transition of Cdc13 between the two complexes (204).
Protein phosphorylation is a key mechanism that determines Cdc13 association with Stn1-Ten1 and telomerase in yeast (205-207) (Fig. 2). Tseng et al (205) showed by an immunoprecipitation-kinase assay that Mec1 and Tel1 (yeast ATR/ATM) phosphorylate Cdc13 SQ/TQ motifs in vitro. Cdc13 is phosphorylated by Mec1 on serine 225, 249 and 255, and 306, whereas Tel1 phosphorylates serine 225, 249 and 255. In addition, mutation of these phosphorylation sites induces multiple telomeric and growth defects in yeast. The finding that normal telomere length and growth could be restored by the expression of a Cdc13-Est1 fusion protein, demonstrates that phosphorylation of SQ/TQ motifs by Mec1/Tel1 within the telomerase recruitment domain of Cdc13, is important for recruiting telomerase to telomeres (205). It has also been demonstrated in yeast that Cdk1-dependent phosphorylation of Cdc13 promotes the interaction of Cdc13 with Est1 to extend telomeric DNA (206-207). Cdk1 phosphorylates S/TP motifs on residues 308 and 336 of Cdc13 and mutation of these sites induces telomere shortening, cell cycle arrest and alters normal Cdc13 protein turnover (207). These findings suggest that Cdk1 phosphorylates the telomerase recruitment domain of Cdc13 facilitating telomere replication and cell cycle progression in addition to maintaining optimal Cdc13 protein levels during the cell cycle (207). Therefore phosphorylation of Cdc13 by Cdk1, Mec1 and/or Tel1 in yeast is important for telomerase dependent DNA extension events (Fig. 2).
The functional interaction between Cdc13 and telomerase in yeast resembles that of POT1 and telomerase in humans (208). When bound near the 3'overhang of telomeric DNA, both the full-length Cdc13 and its DNA-binding domain competitively block access of telomerase to its substrate in vitro (208). However, Cdc13 also shows a novel 'action at a distance' inhibitory activity when the 3'overhang is present in excess (208). Thus, Cdc13 recruits telomerase to telomeres in a switched 'off' mode. Further investigation is needed to determine whether the switch is turned 'on' by Cdc13 phosphorylation or by a similar signal that regulates the POT1-TPP1 complex in mammalian cells. It has also been suggested that Stn1 inhibits telomerase at an early stage by recruiting the Pol a-primase to polymerise the C-strand of telomeres in yeast (206, 209-210).
5.3. Interactions between telomerase and DNA-PK complexes
In mammalian cells, DNA-PK is suggested to be involved in both telomerase recruitment and telomere capping. The Ku70/80 dimer of the DNA-PK complex interacts directly with TERT in human cells. Antibodies against human Ku proteins precipitate telomerase from cell extracts of tumour and telomerase-immortalised normal cells, and also in vitro reconstituted telomerase, suggesting direct protein-protein interaction (178). Consistently, Ku is associated with in vitro translated TERT in the absence of TER or telomeric DNA (178). Furthermore, deletion of both TER and DNA-PKcs in mice increases the rate of telomere shortening compared with the deletion of TER alone, suggesting a telomerase independent role of DNA-PKcs in the maintenance of telomere length (211). In addition, DNA-PK may interact with telomerase indirectly through the DNA-PK interacting protein KIP (DNA-protein kinase catalytic subunit-interacting protein) that binds TERT in the yeast two-hybrid system, co-immunoprecipitates with TERT from cell-free extracts and co-localises with TERT in the nucleus (212). Over-expression of KIP results in increased telomerase activity and telomere lengthening (212).
Studies by Beattie and colleagues (213) revealed an interaction between telomerase and DNA-PK from a different perspective. By using specific DNA-PK inhibitors they found increased rates of telomere loss due to kinase inhibition. This suggests that the kinase activity of DNA-PK is required for its function at telomeres, possibly by phosphorylating proteins required for maintaining telomere length. The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) , a known telomere and telomerase binding protein (214), is a direct substrate for DNA-PK, and phosphorylation of hnRNP A1 by DNA-PK is stimulated by both DNA and also TER (213). In human cell lines lacking TER, DNA-PK-dependent phosphorylation of hnRNP A1 is greatly decreased, indicating that TER stimulates the kinase activity of DNA-PK (213). Thus, telomere maintenance in human cells is dependent upon interactions between components of telomerase and DNA-PK , namely between Ku and TERT and between DNA-PKcs and TER.
5.4. Interactions between telomerase and MRN complexes
MRN plays an important role in telomere maintenance by telomerase. In yeast, the intact MRN complex is implicated in preparing single-stranded telomeric DNA for telomerase-dependent extension (215) and recruitment of the telomere replication machinery (including telomerase) at late S-phase (216). Consistently, knock down of MRN by RNAi in yeast, results in transient shortening of the 3' overhang (217). MRN is also important for telomerase independent telomere maintenance that occurs in yeast upon deficiency of the telomere binding protein taz1 and Trt1 (TERT) (218). In addition to the checkpoint kinase Tel1 (ATM) and RAP1, the MRN complex is required for telomere maintenance in taz1/trt1 double-deletion cells. Expression of catalytically inactive Trt1 efficiently inhibits MRN-mediated recombination-based telomere maintenance, suggesting that MRN-Tel1 and Rap1 promote recombination-based telomere maintenance and that this mechanism of maintenance is inhibited by telomerase (218). Thus, MRN is important for telomere maintenance by reverse transcription and homologous recombination, respectively, which enables the survival of yeast when either mechanism is absent.
In mammals, the association of MRN with TRF2 at telomeres during the S-phase targets MRN to telomeres (166, 172). In patients with Nijmegen breakage syndrome, lack of NBS leads to shortened telomeres. Both NBS1 and TERT are needed for telomere elongation in NBS1-deficient fibroblasts (164). Silencing MRN results in a shortening of the 3' overhang in telomerase-positive (but not telomerase-negative) cells, although the terminal nucleotides of both C- and G-rich strands remain unaltered in cells depleted of MRE11 suggesting that MRN is not responsible for specifying the final end-processing event (168). Shortening of the telomere overhang also occurs after the forced expression of exogenous telomerase, suggesting involvement of the MRN complex in the recruitment or action of telomerase (168).
Distinct protein complexes accumulate at telomeric DNA to cap, protect and facilitate lengthening of telomeres. Several complexes of telomere binding proteins interact with telomerase to regulate telomere homeostasis and thus cell fate. Whereas protein complexes that bind double-stranded DNA have a negative role in regulating telomerase, those that bind a single-stranded DNA can cooperate with telomerase to maintain telomeres. Emerging evidence indicates that the processes of capping and lengthening single-stranded telomeres are the function of distinct cellular machinery that includes the POT1-TPP1, CST and telomerase complexes. It is not yet known why there are two interacting telomerase-recruiting single-stranded telomere binding protein complexes. It is possible that the shelterin and DNA-PK complexes perform a house-keeping role on telomere duplexes, while the MRN and telomerase complexes are critical for telomere maintenance in damaged and short telomeres, respectively. Elucidation of the molecular switches that trigger activation and recruitment of the different complexes would provide insight into how telomeres might be reprogrammed and remodelled to achieve desirable effects on cell proliferation potential. In addition, it is not known what changes in telomere binding proteins take place during aging and tumorigenesis. In model systems, the loss of telomere binding proteins generates an aging phenotype, for example mutations of TIN2 and POT1 in dyskeratosis congenita. Whereas a decline of Ku70 and MRE11 expression has been observed with age in the human population (219), loss of telomere binding proteins following repeated antigenic stimulation of lymphocytes has been shown to cause telomere shortening associated with decreased TRF1, TIN2, POT1, RAP1 and TANK1 (220). These observations highlight the necessity for new studies to identify the true contribution of loss of telomere binding proteins to aging-associated telomere loss and cell senescence.
This work was supported by grants from the National Health and Medical Research Council of Australia and Cancer Council of Victoria. ARP was the recipient of a Monash University postgraduate scholarship.
1. T. de Lange: Protection of mammalian telomeres. Oncogene, 21(4), 532-40 (2002)
doi:10.1038/sj.onc.1205080
PMid:11850778
2. R. E. Verdun and J. Karlseder: Replication and protection of telomeres. Nature, 447(7147), 924-31 (2007)
doi:10.1038/nature05976
PMid:17581575
3. D. Rhodes, L. Fairall, T. Simonsson, R. Court and L. Chapman: Telomere architecture. EMBO Rep, 3(12), 1139-45 (2002)
doi:10.1093/embo-reports/kvf246
PMid:12475927 PMCid:1308316
4. E. Gilson and V. Geli: How telomeres are replicated. Nat Rev Mol Cell Biol, 8(10), 825-38 (2007)
doi:10.1038/nrm2259
PMid:17885666
5. B. R. Linger and C. M. Price: Conservation of telomere protein complexes: shuffling through evolution. Crit Rev Biochem Mol Biol, 44(6), 434-46 (2009)
doi:10.3109/10409230903307329
PMid:19839711 PMCid:2788028
6. N. F. Lue: Plasticity of telomere maintenance mechanisms in yeast. Trends Biochem Sci, 35(1), 8-17 (2010)
doi:10.1016/j.tibs.2009.08.006
PMid:19846312
7. G. De Boeck, R. G. Forsyth, M. Praet and P. C. Hogendoorn: Telomere-associated proteins: cross-talk between telomere maintenance and telomere-lengthening mechanisms. J Pathol, 217(3), 327-44 (2009)
doi:10.1002/path.2500
PMid:19142887
8. J. C. Cookson and C. A. Laughton: The levels of telomere-binding proteins in human tumours and therapeutic implications. Eur J Cancer, 45(4), 536-50 (2009)
doi:10.1016/j.ejca.2008.11.014
PMid:19114299
9. S. E. Artandi and R. A. DePinho: Telomeres and telomerase in cancer. Carcinogenesis, 31(1), 9-18 (2010)
doi:10.1093/carcin/bgp268
PMid:19887512
10. S. Bhattacharyya, A. Sandy and J. Groden: Unwinding protein complexes in ALTernative telomere maintenance. J Cell Biochem, 109(1), 7-15 (2010)
PMid:19911388
11. H. Xin, D. Liu and Z. Songyang: The telosome/shelterin complex and its functions. Genome Biol, 9(9), 232 (2008)
doi:10.1186/gb-2008-9-9-232
PMid:18828880 PMCid:2592706
12. W. Palm and T. de Lange: How shelterin protects mammalian telomeres. Annu Rev Genet, 42, 301-34 (2008)
doi:10.1146/annurev.genet.41.110306.130350
PMid:18680434
13. A. Bianchi and D. Shore: How telomerase reaches its end: mechanism of telomerase regulation by the telomeric complex. Mol Cell, 31(2), 153-65 (2008)
doi:10.1016/j.molcel.2008.06.013
PMid:18657499
14. J. L. Stern and T. M. Bryan: Telomerase recruitment to telomeres. Cytogenet Genome Res, 122(3-4), 243-54 (2008)
doi:10.1159/000167810
PMid:19188693
15. D. Rhodes, L. Fairall, T. Simonsson, R. Court and L. Chapman: Telomere architecture. EMBO Reports, 3(12), 1139-45 (2002)
doi:10.1093/embo-reports/kvf246
PMid:12475927 PMCid:1308316
16. V. L. Makarov, Y. Hirose and J. P. Langmore: Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening. Cell, 88(5), 657-66 (1997)
doi:10.1016/S0092-8674(00)81908-X
17. W. E. Wright, V. M. Tesmer, K. E. Huffman, S. D. Levene and J. W. Shay: Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev, 11(21), 2801-9 (1997)
doi:10.1101/gad.11.21.2801
18. J. D. Griffith, L. Comeau, S. Rosenfield, R. M. Stansel, A. Bianchi, H. Moss and T. de Lange: Mammalian telomeres end in a large duplex loop (see comments). Cell, 97(4), 503-14 (1999)
doi:10.1016/S0092-8674(00)80760-6
19. J. L. Munoz-Jordan, G. A. Cross, T. de Lange and J. D. Griffith: t-loops at trypanosome telomeres. EMBO J, 20(3), 579-88 (2001)
doi:10.1093/emboj/20.3.579
PMid:11157764 PMCid:133480
20. T. de Lange: T-loops and the origin of telomeres. Nat Rev Mol Cell Biol, 5(4), 323-9 (2004)
doi:10.1038/nrm1359
PMid:15071557
21. R. C. Allsopp and C. B. Harley: Evidence for a critical telomere length in senescent human fibroblasts. Exp Cell Res, 219(1), 130-6 (1995)
doi:10.1006/excr.1995.1213
PMid:7628529
22. R. C. Allsopp, H. Vaziri, C. Patterson, S. Goldstein, E. V. Younglai, A. B. Futcher, C. W. Greider and C. B. Harley: Telomere length predicts replicative capacity of human fibroblasts. Proceedings of the National Academy of Sciences of the United States of America, 89, 10114-10118 (1992)
doi:10.1073/pnas.89.21.10114
23. C. B. Harley, A. B. Futcher and C. W. Greider: Telomeres shorten during ageing of human fibroblasts. Nature, 345, 458-460 (1990)
doi:10.1038/345458a0
PMid:2342578
24. N. D. Hastie, M. Dempster, M. G. Dunlop, A. M. Thompson, D. K. Green and R. C. Allshire: Telomere reduction in human colorectal carcinoma and with ageing (see comments). Nature, 346, 866-868 (1990)
doi:10.1038/346866a0
PMid:2392154
25. A. M. Olovnikov: Principle of marginotomy in template synthesis of polynucleotides. Dokl Akad Nauk SSSR, 201(6), 1496-9 (1971)
PMid:5158754
26. J. D. Watson: Origin of concatemeric T7 DNA. Nat New Biol, 239(94), 197-201 (1972)
PMid:4507727
27. M. A. Blasco, H. W. Lee, M. P. Hande, E. Samper, P. M. Lansdorp, R. A. DePinho and C. W. Greider: Telomere shortening and tumor formation by mouse cells lacking telomerase RNA (see comments). Cell, 91(1), 25-34 (1997)
doi:10.1016/S0092-8674(01)80006-4
28. H. Niida, T. Matsumoto, H. Satoh, M. Shiwa, Y. Tokutake, Y. Furuichi and Y. Shinkai: Severe growth defect in mouse cells lacking the telomerase RNA component. Nat Genet, 19(2), 203-6 (1998)
doi:10.1038/580
PMid:9620783
29. L. Hayflick and P. S. Moorhead: The serial cultivation of human diploid cell strains. Experimental Cell Research, 25(3), 585-621 (1961)
doi:10.1016/0014-4827(61)90192-6
30. C. D. Belair, T. R. Yeager, P. M. Lopez and C. A. Reznikoff: Telomerase activity: a biomarker of cell proliferation, not malignant transformation. Proc Natl Acad Sci U S A, 94(25), 13677-82 (1997)
doi:10.1073/pnas.94.25.13677
31. S. E. Holt, J. W. Shay and W. E. Wright: Refining the telomere-telomerase hypothesis of aging and cancer. Nat Biotechnol, 14(7), 836-9 (1996)
doi:10.1038/nbt0796-836
PMid:9631006
32. M. Amit, M. K. Carpenter, M. S. Inokuma, C. P. Chiu, C. P. Harris, M. A. Waknitz, J. Itskovitz-Eldor and J. A. Thomson: Clonally derived human embryonic stem cell lines maintain pluripotency and proliferative potential for prolonged periods of culture. Dev Biol, 227(2), 271-8 (2000)
doi:10.1006/dbio.2000.9912
PMid:11071754
33. K. Takahashi, K. Tanabe, M. Ohnuki, M. Narita, T. Ichisaka, K. Tomoda and S. Yamanaka: Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861-72 (2007)
doi:10.1016/j.cell.2007.11.019
PMid:18035408
34. J. Yu, M. A. Vodyanik, K. Smuga-Otto, J. Antosiewicz-Bourget, J. L. Frane, S. Tian, J. Nie, G. A. Jonsdottir, V. Ruotti, R. Stewart, Slukvin, II and J. A. Thomson: Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917-20 (2007)
doi:10.1126/science.1151526
PMid:18029452
35. P. A. Kruk, A. S. Balajee, K. S. Rao and V. A. Bohr: Telomere reduction and telomerase inactivation during neuronal cell differentiation. Biochem Biophys Res Commun, 224(2), 487-92 (1996)
doi:10.1006/bbrc.1996.1054
PMid:8702416
36. H. Li, A. R. Pinto, W. Duan, J. Li, B. H. Toh and J. P. Liu: Telomerase down-regulation does not mediate PC12 pheochromocytoma cell differentiation induced by NGF, but requires MAP kinase signalling. J Neurochem, 95(3), 891-901 (2005)
doi:10.1111/j.1471-4159.2005.03439.x
PMid:16248892
37. H. W. Sharma, J. A. Sokoloski, J. R. Perez, J. Y. Maltese, A. C. Sartorelli, C. A. Stein, G. Nichols, Z. Khaled, N. T. Telang and R. Narayanan: Differentiation of immortal cells inhibits telomerase activity. Proc.Natl.Acad.Sci.U.S.A., 92, 12343-12346 (1996)
doi:10.1073/pnas.92.26.12343
38. S. Wang, C. Hu and J. Zhu: Transcriptional silencing of a novel hTERT reporter locus during in vitro differentiation of mouse embryonic stem cells. Mol Biol Cell, 18(2), 669-77 (2007)
doi:10.1091/mbc.E06-09-0840
PMid:17151355 PMCid:1783791
39. K. Masutomi, E. Y. Yu, S. Khurts, I. Ben-Porath, J. L. Currier, G. B. Metz, M. W. Brooks, S. Kaneko, S. Murakami, J. A. DeCaprio, R. A. Weinberg, S. A. Stewart and W. C. Hahn: Telomerase maintains telomere structure in normal human cells. Cell, 114(2), 241-53 (2003)
doi:10.1016/S0092-8674(03)00550-6
40. C. P. Morales, S. E. Holt, M. Ouellette, K. J. Kaur, Y. Yan, K. S. Wilson, M. A. White, W. E. Wright and J. W. Shay: Absence of cancer-associated changes in human fibroblasts immortalized with telomerase. Nat Genet, 21(1), 115-8 (1999)
doi:10.1038/5063
PMid:9916803
41. A. G. Bodnar, M. Ouellette, M. Frolkis, S. E. Holt, C.-P. Chiu, G. B. Morin, C. B. Harley, J. W. Shay, S. Lichtsteiner and W. E. Wright: Extension of life-span by introduction of telomerase into normal human cells. Science, 279(5349), 349-352 (1998)
doi:10.1126/science.279.5349.349
PMid:9454332
42. J. W. Shay and W. E. Wright: Senescence and immortalization: role of telomeres and telomerase. Carcinogenesis, 26(5), 867-74 (2005)
doi:10.1093/carcin/bgh296
PMid:15471900
43. N. W. Kim, M. A. Piatyszek, K. R. Prowse, C. B. Harley, M. D. West, P. L. Ho, G. M. Coviello, W. E. Wright, S. L. Weinrich and J. W. Shay: Specific association of human telomerase activity with immortal cells and cancer. Science, 266, 2011-2015 (1994)
doi:10.1126/science.7605428
PMid:7605428
44. X. Zhang, V. Mar, W. Zhou, L. Harrington and M. O. Robinson: Telomere shortening and apoptosis in telomerase-inhibited human tumor cells. Genes Dev, 13(18), 2388-2399 (1999)
doi:10.1101/gad.13.18.2388
45. J. P. Liu, C. Nicholls, S. M. Chen, H. Li and Z. Z. Tao: Strategies of Treating Cancer by Cytokine Regulation of Chromosome End Remodelling. Clin Exp Pharmacol Physiol, 37, 88-92 (2010)
doi:10.1111/j.1440-1681.2009.05251.x
PMid:19566820
46. J. D. Henson, Y. Cao, L. I. Huschtscha, A. C. Chang, A. Y. Au, H. A. Pickett and R. R. Reddel: DNA C-circles are specific and quantifiable markers of alternative-lengthening-of-telomeres activity. Nat Biotechnol, 27(12), 1181-5 (2009)
doi:10.1038/nbt.1587
PMid:19935656
47. W. Q. Jiang, Z. H. Zhong, A. Nguyen, J. D. Henson, C. D. Toouli, A. W. Braithwaite and R. R. Reddel: Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins. J Cell Biol, 185(5), 797-810 (2009)
doi:10.1083/jcb.200810084
PMid:19468068 PMCid:2711592
48. H. A. Pickett, A. J. Cesare, R. L. Johnston, A. A. Neumann and R. R. Reddel: Control of telomere length by a trimming mechanism that involves generation of t-circles. EMBO J, 28(7), 799-809 (2009)
doi:10.1038/emboj.2009.42
PMid:19214183 PMCid:2670870
49. M. A. Blasco: Telomeres and human disease: ageing, cancer and beyond. Nat Rev Genet, 6(8), 611-22 (2005)
doi:10.1038/nrg1656
PMid:16136653
50. T. De Lange: Telomere-related genome instability in cancer. Cold Spring Harb Symp Quant Biol, 70, 197-204 (2005)
doi:10.1101/sqb.2005.70.032
PMid:16869754
51. D. Liu, M. S. O'Connor, J. Qin and Z. Songyang: Telosome, a mammalian telomere-associated complex formed by multiple telomeric proteins. J Biol Chem, 279(49), 51338-42 (2004)
doi:10.1074/jbc.M409293200
PMid:15383534
52. M. S. O'Connor, A. Safari, D. Liu, J. Qin and Z. Songyang: The human Rap1 protein complex and modulation of telomere length. J Biol Chem, 279(27), 28585-91 (2004)
doi:10.1074/jbc.M312913200
PMid:15100233
53. J. Z. Ye, D. Hockemeyer, A. N. Krutchinsky, D. Loayza, S. M. Hooper, B. T. Chait and T. de Lange: POT1-interacting protein PIP1: a telomere length regulator that recruits POT1 to the TIN2/TRF1 complex. Genes Dev, 18(14), 1649-54 (2004)
doi:10.1101/gad.1215404
54. S. B. Cohen, M. E. Graham, G. O. Lovrecz, N. Bache, P. J. Robinson and R. R. Reddel: Protein composition of catalytically active human telomerase from immortal cells. Science, 315(5820), 1850-3 (2007)
doi:10.1126/science.1138596
PMid:17395830
55. A. S. Venteicher, Z. Meng, P. J. Mason, T. D. Veenstra and S. E. Artandi: Identification of ATPases Pontin and Reptin as Telomerase Components Essential for Holoenzyme Assembly. Cell, 132(6), 945-957 (2008)
doi:10.1016/j.cell.2008.01.019
PMid:18358808 PMCid:2291539
56. J. D. Podlevsky, C. J. Bley, R. V. Omana, X. Qi and J. J. Chen: The telomerase database. Nucleic Acids Res, 36(Database issue), D339-43 (2008)
57. A. S. Venteicher, E. B. Abreu, Z. Meng, K. E. McCann, R. M. Terns, T. D. Veenstra, M. P. Terns and S. E. Artandi: A human telomerase holoenzyme protein required for Cajal body localization and telomere synthesis. Science, 323(5914), 644-8 (2009)
doi:10.1126/science.1165357
PMid:19179534 PMCid:2728071
58. S. E. Holt, D. L. Aisner, J. Baur, V. M. Tesmer, M. Dy, M. Ouellette, J. B. Trager, G. B. Morin, D. O. Toft, J. W. Shay, W. E. Wright and M. A. White: Functional requirement of p23 and hsp90 in telomerase complexes. Genes Dev, 13(7), 817-26 (1999)
doi:10.1101/gad.13.7.817
59. H. L. Forsythe, J. L. Jarvis, J. W. Turner, L. W. Elmore and S. E. Holt: Stable association of hsp90 and p23, but not hsp70, with active human telomerase. J Biol Chem, 276(19), 15571-4 (2001)
doi:10.1074/jbc.C100055200
PMid:11274138
60. J. Feng: The RNA component of human telomerase. Science, 269, 1236-1241 (1995)
doi:10.1126/science.7544491
PMid:7544491
61. L. Harrington: Human telomerase contains evolutionarily conserved catalytic and structural subunits. Genes Dev., 11, 3109-3115 (1997)
doi:10.1101/gad.11.23.3109
62. S. Ramakrishnan, U. Eppenberger, H. Mueller, Y. Shinkai and R. Narayanan: Expression profile of the putative catalytic subunit of the telomerase gene. Cancer Res, 58(4), 622-5 (1998)
PMid:9485011
63. M. Takakura, S. Kyo, T. Kanaya, M. Tanaka and M. Inoue: Expression of human telomerase subunits and correlation with telomerase activity in cervical cancer. Cancer Res, 58(7), 1558-61 (1998)
PMid:9537264
64. G. A. Ulaner, J. F. Hu, T. H. Vu, L. C. Giudice and A. R. Hoffman: Telomerase activity in human development is regulated by human telomerase reverse transcriptase (hTERT) transcription and by alternate splicing of hTERT transcripts. Cancer Res, 58(18), 4168-72 (1998)
PMid:9751630
65. K. J. Wu, C. Grandori, M. Amacker, N. Simon-Vermot, A. Polack, J. Lingner and R. Dalla-Favera: Direct activation of TERT transcription by c-MYC. Nat Genet, 21(2), 220-4 (1999)
doi:10.1038/6010
PMid:9988278
66. M. Meyerson, C. M. Counter, E. N. Eaton, L. W. Ellisen, P. Steiner, S. D. Caddle, L. Ziaugra, R. L. Beijersbergen, M. J. Davidoff, Q. Liu, S. Bacchetti, D. A. Haber and R. A. Weinberg: hEst2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell, 90(4), 785-95 (1997)
doi:10.1016/S0092-8674(00)80538-3
67. T. M. Nakamura, G. B. Morin, K. B. Chapman, S. L. Weinrich, W. H. Andrews, J. Lingner, C. B. Harley and T. R. Cech: Telomerase catalytic subunit homologs from fission yeast and human. Science, 277(5328), 955-9 (1997)
doi:10.1126/science.277.5328.955
PMid:9252327
68. J. P. Liu, S. M. Chen, Y. S. Cong, C. Nicholls, S. F. Zhou, Z. Z. Tao and H. Li: Regulation of telomerase activity by apparently opposing elements. Ageing Res Rev (2010)
69. J. A. Box, J. T. Bunch, W. Tang and P. Baumann: Spliceosomal cleavage generates the 3' end of telomerase RNA. Nature, 456(7224), 910-4 (2008)
doi:10.1038/nature07584
PMid:19052544
70. G. A. Ulaner, J. F. Hu, T. H. Vu, L. C. Giudice and A. R. Hoffman: Tissue-specific alternate splicing of human telomerase reverse transcriptase (hTERT) influences telomere lengths during human development. Int J Cancer, 91(5), 644-9. (2001)
doi:10.1002/1097-0215(200002)9999:9999<::AID-IJC1103>3.0.CO;2-V
71. C. Autexier and N. F. Lue: The structure and function of telomerase reverse transcriptase. Annu Rev Biochem, 75, 493-517 (2006)
doi:10.1146/annurev.biochem.75.103004.142412
PMid:16756500
72. C. M. Azzalin, P. Reichenbach, L. Khoriauli, E. Giulotto and J. Lingner: Telomeric repeat containing RNA and RNA surveillance factors at mammalian chromosome ends. Science, 318(5851), 798-801 (2007)
doi:10.1126/science.1147182
PMid:17916692
73. S. Schoeftner and M. A. Blasco: Developmentally regulated transcription of mammalian telomeres by DNA-dependent RNA polymerase II. Nat Cell Biol, 10(2), 228-36 (2008)
doi:10.1038/ncb1685
PMid:18157120
74. L. J. Ng, J. E. Cropley, H. A. Pickett, R. R. Reddel and C. M. Suter: Telomerase activity is associated with an increase in DNA methylation at the proximal subtelomere and a reduction in telomeric transcription. Nucleic Acids Res (2009)
75. Y. Cong and J. W. Shay: Actions of human telomerase beyond telomeres. Cell Res, 18(7), 725-32 (2008)
doi:10.1038/cr.2008.74
PMid:18574498
76. L. Cassar, H. Li, F. X. Jiang and J. P. Liu: TGF-beta induces telomerase-dependent pancreatic tumor cell cycle arrest. Mol Cell Endocrinol, 320, 95-105 (2010)
doi:10.1016/j.mce.2010.02.002
PMid:20138964
77. J. A. Baur, Y. Zou, J. W. Shay and W. E. Wright: Telomere position effect in human cells. Science, 292(5524), 2075-7 (2001)
doi:10.1126/science.1062329
PMid:11408657
78. C. M. Counter, W. C. Hahn, W. Wei, S. D. Caddle, R. L. Beijersbergen, P. M. Lansdorp, J. M. Sedivy and R. A. Weinberg: Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. Proc Natl Acad Sci U S A, 95(25), 14723-8 (1998)
doi:10.1073/pnas.95.25.14723
79. M. R. Stampfer, J. Garbe, G. Levine, S. Lichtsteiner, A. P. Vasserot and P. Yaswen: Expression of the telomerase catalytic subunit, hTERT, induces resistance to transforming growth factor beta growth inhibition in p16INK4A(-) human mammary epithelial cells. Proc Natl Acad Sci U S A, 98(8), 4498-503. (2001)
doi:10.1073/pnas.071483998
PMid:11287649 PMCid:31863
80. Y. Cao, H. Li, S. Deb and J. P. Liu: TERT regulates cell survival independent telomerase activity. Oncogene, 21, 3130-3138 (2002)
doi:10.1038/sj.onc.1205419
PMid:12082628
81. J. Lee, Y. H. Sung, C. Cheong, Y. S. Choi, H. K. Jeon, W. Sun, W. C. Hahn, F. Ishikawa and H. W. Lee: TERT promotes cellular and organismal survival independently of telomerase activity. Oncogene, 27(26), 3754-60 (2008)
doi:10.1038/sj.onc.1211037
PMid:18223679
82. C. Massard, Y. Zermati, A. L. Pauleau, N. Larochette, D. Metivier, L. Sabatier, G. Kroemer and J. C. Soria: hTERT: a novel endogenous inhibitor of the mitochondrial cell death pathway. Oncogene, 25(33), 4505-14 (2006)
doi:10.1038/sj.onc.1209487
PMid:16619047
83. J. I. Park, A. S. Venteicher, J. Y. Hong, J. Choi, S. Jun, M. Shkreli, W. Chang, Z. Meng, P. Cheung, H. Ji, M. McLaughlin, T. D. Veenstra, R. Nusse, P. D. McCrea and S. E. Artandi: Telomerase modulates Wnt signalling by association with target gene chromatin. Nature, 460(7251), 66-72 (2009)
doi:10.1038/nature08137
PMid:19571879
84. G. J. Narlikar, H.-Y. Fan and R. E. Kingston: Cooperation between Complexes that Regulate Chromatin Structure and Transcription. Cell, 108(4), 475-487 (2002)
doi:10.1016/S0092-8674(02)00654-2
85. T. Ito, H. Watanabe, N. Yamamichi, S. Kondo, T. Tando, T. Haraguchi, T. Mizutani, K. Sakurai, S. Fujita, T. Izumi, T. Isobe and H. Iba: Brm transactivates the telomerase reverse transcriptase (TERT) gene and modulates the splicing patterns of its transcripts in concert with p54(nrb). Biochem J, 411(1), 201-9 (2008)
doi:10.1042/BJ20071075
PMid:18042045
86. S. L. Vidal-Cardenas and C. W. Greider: Comparing effects of mTR and mTERT deletion on gene expression and DNA damage response: a critical examination of telomere length maintenance-independent roles of telomerase. Nucleic Acids Res, 38(1), 60-71 (2009)
doi:10.1093/nar/gkp855
PMid:19850716 PMCid:2800220
87. W. Oh, J. Ghim, E. W. Lee, M. R. Yang, E. T. Kim, J. H. Ahn and J. Song: PML-IV functions as a negative regulator of telomerase by interacting with TERT. J Cell Sci, 122(Pt 15), 2613-22 (2009)
doi:10.1242/jcs.048066
PMid:19567472
88. O. Bischof, O. Kirsh, M. Pearson, K. Itahana, P. G. Pelicci and A. Dejean: Deconstructing PML-induced premature senescence. Embo J, 21(13), 3358-69 (2002)
doi:10.1093/emboj/cdf341
PMid:12093737 PMCid:126090
89. D. Xu, S. Erickson, M. Szeps, A. Gruber, O. Sangfelt, S. Einhorn, P. Pisa and D. Grander: Interferon alpha down-regulates telomerase reverse transcriptase and telomerase activity in human malignant and nonmalignant hematopoietic cells (In Process Citation). Blood, 96(13), 4313-8 (2000)
PMid:11110707
90. R. Hrdlickova, J. Nehyba and H. R. Bose, Jr.: Regulation of telomerase activity by interferon regulatory factors 4 and 8 in immune cells. Mol Cell Biol, 29(3), 929-41 (2009)
doi:10.1128/MCB.00961-08
PMid:19047367 PMCid:2630682
91. M. K. Mateyak and V. A. Zakian: Human PIF helicase is cell cycle regulated and associates with telomerase. Cell Cycle, 5(23), 2796-804 (2006)
PMid:17172855
92. D. H. Zhang, B. Zhou, Y. Huang, L. X. Xu and J. Q. Zhou: The human Pif1 helicase, a potential Escherichia coli RecD homologue, inhibits telomerase activity. Nucleic Acids Res, 34(5), 1393-404 (2006)
doi:10.1093/nar/gkl029
PMid:16522649 PMCid:1390689
93. J. Zhou, E. K. Monson, S. Teng, V. P. Schulz and V. A. Zakian: Pif1p Helicase, a Catalytic Inhibitor of Telomerase in Yeast. Science, 289(5480), 771-774 (2000)
doi:10.1126/science.289.5480.771
PMid:10926538
94. J. B. Boule, L. R. Vega and V. A. Zakian: The yeast Pif1p helicase removes telomerase from telomeric DNA. Nature, 438(7064), 57-61 (2005)
doi:10.1038/nature04091
PMid:16121131
95. B. E. Snow, M. Mateyak, J. Paderova, A. Wakeham, C. Iorio, V. Zakian, J. Squire and L. Harrington: Murine Pif1 interacts with telomerase and is dispensable for telomere function in vivo. Mol Cell Biol, 27(3), 1017-26 (2007)
doi:10.1128/MCB.01866-06
PMid:17130244 PMCid:1800700
96. N. Sen, M. R. Hara, M. D. Kornberg, M. B. Cascio, B. I. Bae, N. Shahani, B. Thomas, T. M. Dawson, V. L. Dawson, S. H. Snyder and A. Sawa: Nitric oxide-induced nuclear GAPDH activates p300/CBP and mediates apoptosis. Nat Cell Biol, 10(7), 866-73 (2008)
doi:10.1038/ncb1747
PMid:18552833 PMCid:2689382
97. C. Xing, J. R. LaPorte, J. K. Barbay and A. G. Myers: Identification of GAPDH as a protein target of the saframycin antiproliferative agents. Proc Natl Acad Sci U S A, 101(16), 5862-6 (2004)
doi:10.1073/pnas.0307476101
PMid:15079082 PMCid:395888
98. N. A. Demarse, S. Ponnusamy, E. K. Spicer, E. Apohan, J. E. Baatz, B. Ogretmen and C. Davies: Direct binding of glyceraldehyde 3-phosphate dehydrogenase to telomeric DNA protects telomeres against chemotherapy-induced rapid degradation. J Mol Biol, 394(4), 789-803 (2009)
doi:10.1016/j.jmb.2009.09.062
PMid:19800890
99. K. P. Sundararaj, R. E. Wood, S. Ponnusamy, A. M. Salas, Z. Szulc, A. Bielawska, L. M. Obeid, Y. A. Hannun and B. Ogretmen: Rapid shortening of telomere length in response to ceramide involves the inhibition of telomere binding activity of nuclear glyceraldehyde-3-phosphate dehydrogenase. J Biol Chem, 279(7), 6152-62 (2004)
doi:10.1074/jbc.M310549200
PMid:14630908
100. J. R. Mitchell, J. Cheng and K. Collins: A box H/ACA small nucleolar RNA-like domain at the human telomerase RNA 3' end. Mol Cell Biol, 19(1), 567-76 (1999)
PMid:9858580 PMCid:83914
101. J. L. Chen, M. A. Blasco and C. W. Greider: Secondary structure of vertebrate telomerase RNA (In Process Citation). Cell, 100(5), 503-14 (2000)
doi:10.1016/S0092-8674(00)80687-X
102. B. E. Jady, E. Bertrand and T. Kiss: Human telomerase RNA and box H/ACA scaRNAs share a common Cajal body-specific localization signal. J. Cell Biol., 164(5), 647-652 (2004)
doi:10.1083/jcb.200310138
PMid:14981093 PMCid:2172171
103. T. Kiss: Small nucleolar RNAs: an abundant group of noncoding RNAs with diverse cellular functions. Cell, 109(2), 145-8 (2002)
doi:10.1016/S0092-8674(02)00718-3
104. X. Darzacq, B. E. Jady, C. Verheggen, A. M. Kiss, E. Bertrand and T. Kiss: Cajal body-specific small nuclear RNAs: a novel class of 2'-O-methylation and pseudouridylation guide RNAs. EMBO J, 21(11), 2746-56 (2002)
doi:10.1093/emboj/21.11.2746
PMid:12032087 PMCid:126017
105. U. T. Meier: The many facets of H/ACA ribonucleoproteins. Chromosoma, 114(1), 1-14 (2005)
doi:10.1007/s00412-005-0333-9
PMid:15770508
106. P. Richard, X. Darzacq, E. Bertrand, B. E. Jady, C. Verheggen and T. Kiss: A common sequence motif determines the Cajal body-specific localization of box H/ACA scaRNAs. EMBO J, 22(16), 4283-93 (2003)
doi:10.1093/emboj/cdg394
PMid:12912925 PMCid:175784
107. B. E. Jady, P. Richard, E. Bertrand and T. Kiss: Cell cycle-dependent recruitment of telomerase RNA and Cajal bodies to human telomeres. Mol Biol Cell, 17(2), 944-54 (2006)
doi:10.1091/mbc.E05-09-0904
PMid:16319170 PMCid:1356602
108. R. L. Tomlinson, T. D. Ziegler, T. Supakorndej, R. M. Terns and M. P. Terns: Cell cycle-regulated trafficking of human telomerase to telomeres. Mol Biol Cell, 17(2), 955-65 (2006)
doi:10.1091/mbc.E05-09-0903
PMid:16339074 PMCid:1356603
109. J. L. Chen and C. W. Greider: Telomerase RNA structure and function: implications for dyskeratosis congenita. Trends Biochem Sci, 29(4), 183-92 (2004)
doi:10.1016/j.tibs.2004.02.003
PMid:15082312
110. J. R. Mitchell, E. Wood and K. Collins: A telomerase component is defective in the human disease dyskeratosis congenita. Nature, 402, 551-555 (1999)
doi:10.1038/990141
PMid:10591218
111. C. Hoareau-Aveilla, M. Bonoli, M. Caizergues-Ferrer and Y. Henry: hNaf1 is required for accumulation of human box H/ACA snoRNPs, scaRNPs, and telomerase. RNA, 12(5), 832-840 (2006)
doi:10.1261/rna.2344106
PMid:16601202 PMCid:1440901
112. J. Z. Ye and T. de Lange: TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex. Nat Genet, 36(6), 618-23 (2004)
doi:10.1038/ng1360
PMid:15133513
113. T. Bilaud, C. E. Koering, E. Binet-Brasselet, K. Ancelin, A. Pollice, S. M. Gasser and E. Gilson: The telobox, a Myb-related telomeric DNA binding motif found in proteins from yeast, plants and human. Nucleic Acids Res, 24(7), 1294-303 (1996)
doi:10.1093/nar/24.7.1294
PMid:8614633 PMCid:145771
114. D. Broccoli, A. Smogorzewska, L. Chong and T. de Lange: Human telomeres contain two distinct Myb-related proteins, TRF1 and TRF2. Nat Genet, 17(2), 231-5 (1997)
doi:10.1038/ng1097-231
PMid:9326950
115. A. Sfeir, S. T. Kosiyatrakul, D. Hockemeyer, S. L. MacRae, J. Karlseder, C. L. Schildkraut and T. de Lange: Mammalian telomeres resemble fragile sites and require TRF1 for efficient replication. Cell, 138(1), 90-103 (2009)
doi:10.1016/j.cell.2009.06.021
PMid:19596237
116. K. Ancelin, M. Brunori, S. Bauwens, C. E. Koering, C. Brun, M. Ricoul, J. P. Pommier, L. Sabatier and E. Gilson: Targeting assay to study the cis functions of human telomeric proteins: evidence for inhibition of telomerase by TRF1 and for activation of telomere degradation by TRF2. Mol Cell Biol, 22(10), 3474-87 (2002)
doi:10.1128/MCB.22.10.3474-3487.2002
PMid:11971978 PMCid:133804
117. J. Karlseder, A. Smogorzewska and T. de Lange: Senescence induced by altered telomere state, not telomere loss. Science, 295(5564), 2446-9 (2002)
doi:10.1126/science.1069523
PMid:11923537
118. A. Smogorzewska, B. van Steensel, A. Bianchi, S. Oelmann, M. R. Schaefer, G. Schnapp and T. de Lange: Control of human telomere length by TRF1 and TRF2 (In Process Citation). Mol Cell Biol, 20(5), 1659-68 (2000)
doi:10.1128/MCB.20.5.1659-1668.2000
PMid:10669743 PMCid:85349
119. B. van Steensel and T. de Lange: Control of telomere length by the human telomeric protein TRF1. Nature, 385, 740-743 (1997)
doi:10.1038/385740a0
PMid:9034193
120. P. Martinez, M. Thanasoula, P. Munoz, C. Liao, A. Tejera, C. McNees, J. M. Flores, O. Fernandez-Capetillo, M. Tarsounas and M. A. Blasco: Increased telomere fragility and fusions resulting from TRF1 deficiency lead to degenerative pathologies and increased cancer in mice. Genes Dev, 23(17), 2060-75 (2009)
doi:10.1101/gad.543509
121. P. Munoz, R. Blanco, G. de Carcer, S. Schoeftner, R. Benetti, J. M. Flores, M. Malumbres and M. A. Blasco: TRF1 controls telomere length and mitotic fidelity in epithelial homeostasis. Mol Cell Biol, 29(6), 1608-25 (2009)
doi:10.1128/MCB.01339-08
PMid:19124610 PMCid:2648247
122. J. Karlseder, D. Broccoli, Y. Dai, S. Hardy and T. de Lange: p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science, 283(5406), 1321-5 (1999)
doi:10.1126/science.283.5406.1321
PMid:10037601
123. B. van Steensel, A. Smogorzewska and T. de Lange: TRF2 protects human telomeres from end-to-end fusions. Cell, 92(3), 401-13 (1998)
doi:10.1016/S0092-8674(00)80932-0
124. R. M. Stansel, T. de Lange and J. D. Griffith: T-loop assembly in vitro involves binding of TRF2 near the 3' telomeric overhang. Embo J, 20(19), 5532-40 (2001)
doi:10.1093/emboj/20.19.5532
PMid:11574485 PMCid:125642
125. G. Buscemi, L. Zannini, E. Fontanella, D. Lecis, S. Lisanti and D. Delia: The shelterin protein TRF2 inhibits Chk2 activity at telomeres in the absence of DNA damage. Curr Biol, 19(10), 874-9 (2009)
doi:10.1016/j.cub.2009.03.064
PMid:19375317
126. P. S. Bradshaw, D. J. Stavropoulos and M. S. Meyn: Human telomeric protein TRF2 associates with genomic double-strand breaks as an early response to DNA damage. Nat Genet, 37(2), 193-7 (2005)
doi:10.1038/ng1506
PMid:15665826
127. P. Baumann and T. R. Cech: Pot1, the putative telomere end-binding protein in fission yeast and humans. Science, 292(5519), 1171-5 (2001)
doi:10.1126/science.1060036
PMid:11349150
128. F. Wang, E. R. Podell, A. J. Zaug, Y. Yang, P. Baciu, T. R. Cech and M. Lei: The POT1-TPP1 telomere complex is a telomerase processivity factor. Nature, 445(7127), 506-10 (2007)
doi:10.1038/nature05454
PMid:17237768
129. H. Xin, D. Liu, M. Wan, A. Safari, H. Kim, W. Sun, M. S. O'Connor and Z. Songyang: TPP1 is a homologue of ciliate TEBP-beta and interacts with POT1 to recruit telomerase. Nature, 445(7127), 559-62 (2007)
doi:10.1038/nature05469
PMid:17237767
130. M. Lei, E. R. Podell and T. R. Cech: Structure of human POT1 bound to telomeric single-stranded DNA provides a model for chromosome end-protection. Nat Struct Mol Biol, 11(12), 1223-9 (2004)
doi:10.1038/nsmb867
131. D. Loayza and T. de Lange: Telomerase regulation at the telomere: a binary switch. Cell, 117(3), 279-80 (2004)
doi:10.1016/S0092-8674(04)00409-X
132. D. Loayza and T. De Lange: POT1 as a terminal transducer of TRF1 telomere length control. Nature, 423(6943), 1013-8 (2003)
doi:10.1038/nature01688
PMid:12768206
133. X. Guo, Y. Deng, Y. Lin, W. Cosme-Blanco, S. Chan, H. He, G. Yuan, E. J. Brown and S. Chang: Dysfunctional telomeres activate an ATM-ATR-dependent DNA damage response to suppress tumorigenesis. EMBO J, 26(22), 4709-19 (2007)
doi:10.1038/sj.emboj.7601893
PMid:17948054 PMCid:2080807
134. D. Hockemeyer, W. Palm, T. Else, J. P. Daniels, K. K. Takai, J. Z. Ye, C. E. Keegan, T. de Lange and G. D. Hammer: Telomere protection by mammalian Pot1 requires interaction with Tpp1. Nat Struct Mol Biol, 14(8), 754-61 (2007)
doi:10.1038/nsmb1270
135. T. Kibe, G. A. Osawa, C. E. Keegan and T. de Lange: Telomere protection by TPP1 is mediated by POT1a and POT1b. Mol Cell Biol, 30(4), 1059-66 (2010)
doi:10.1128/MCB.01498-09
PMid:19995905
136. D. Hockemeyer, J. P. Daniels, H. Takai and T. de Lange: Recent expansion of the telomeric complex in rodents: Two distinct POT1 proteins protect mouse telomeres. Cell, 126(1), 63-77 (2006)
doi:10.1016/j.cell.2006.04.044
PMid:16839877
137. L. Wu, A. S. Multani, H. He, W. Cosme-Blanco, Y. Deng, J. M. Deng, O. Bachilo, S. Pathak, H. Tahara, S. M. Bailey, R. R. Behringer and S. Chang: Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell, 126(1), 49-62 (2006)
doi:10.1016/j.cell.2006.05.037
PMid:16839876
138. D. Hockemeyer, W. Palm, R. C. Wang, S. S. Couto and T. de Lange: Engineered telomere degradation models dyskeratosis congenita. Genes Dev, 22(13), 1773-85 (2008)
doi:10.1101/gad.1679208
139. S. H. Kim, P. Kaminker and J. Campisi: TIN2, a new regulator of telomere length in human cells. Nat Genet, 23(4), 405-12 (1999)
doi:10.1038/70508
PMid:10581025
140. S. H. Kim, C. Beausejour, A. R. Davalos, P. Kaminker, S. J. Heo and J. Campisi: TIN2 mediates functions of TRF2 at human telomeres. J Biol Chem, 279(42), 43799-804 (2004)
doi:10.1074/jbc.M408650200
PMid:15292264
141. B. R. Houghtaling, L. Cuttonaro, W. Chang and S. Smith: A dynamic molecular link between the telomere length regulator TRF1 and the chromosome end protector TRF2. Curr Biol, 14(18), 1621-31 (2004)
doi:10.1016/j.cub.2004.08.052
PMid:15380063
142. Y. J. Chiang, M. T. Hemann, K. S. Hathcock, L. Tessarollo, L. Feigenbaum, W. C. Hahn and R. J. Hodes: Expression of telomerase RNA template, but not telomerase reverse transcriptase, is limiting for telomere length maintenance in vivo. Mol Cell Biol, 24(16), 7024-31 (2004)
doi:10.1128/MCB.24.16.7024-7031.2004
PMid:15282303 PMCid:479722
143. S. A. Savage, N. Giri, G. M. Baerlocher, N. Orr, P. M. Lansdorp and B. P. Alter: TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita. Am J Hum Genet, 82(2), 501-9 (2008)
doi:10.1016/j.ajhg.2007.10.004
PMid:18252230 PMCid:2427222
144. A. J. Walne, T. Vulliamy, R. Beswick, M. Kirwan and I. Dokal: TINF2 mutations result in very short telomeres: analysis of a large cohort of patients with dyskeratosis congenita and related bone marrow failure syndromes. Blood, 112(9), 3594-600 (2008)
doi:10.1182/blood-2008-05-153445
PMid:18669893 PMCid:2572788
145. S. Hanaoka, A. Nagadoi, S. Yoshimura, S. Aimoto, B. Li, T. de Lange and Y. Nishimura: NMR structure of the hRap1 Myb motif reveals a canonical three-helix bundle lacking the positive surface charge typical of Myb DNA-binding domains. J Mol Biol, 312(1), 167-75 (2001)
doi:10.1006/jmbi.2001.4924
PMid:11545594
146. K. K. Takai, S. Hooper, S. Blackwood, R. Gandhi and T. de Lange: In vivo stoichiometry of shelterin components. J Biol Chem, 285(2), 1457-67 (2010)
doi:10.1074/jbc.M109.038026
PMid:19864690
147. H. Gao, R. B. Cervantes, E. K. Mandell, J. H. Otero and V. Lundblad: RPA-like proteins mediate yeast telomere function. Nat Struct Mol Biol, 14(3), 208-14 (2007)
doi:10.1038/nsmb1205
148. W. Qian, J. Wang, N. N. Jin, X. H. Fu, Y. C. Lin, J. J. Lin and J. Q. Zhou: Ten1p promotes the telomeric DNA-binding activity of Cdc13p: implication for its function in telomere length regulation. Cell Res, 19(7), 849-63 (2009)
doi:10.1038/cr.2009.67
PMid:19532124
149. L. Xu, R. C. Petreaca, H. J. Gasparyan, S. Vu and C. I. Nugent: TEN1 is essential for CDC13-mediated telomere capping. Genetics, 183(3), 793-810 (2009)
doi:10.1534/genetics.109.108894
PMid:19752213 PMCid:2778977
150. Y. Miyake, M. Nakamura, A. Nabetani, S. Shimamura, M. Tamura, S. Yonehara, M. Saito and F. Ishikawa: RPA-like mammalian Ctc1-Stn1-Ten1 complex binds to single-stranded DNA and protects telomeres independently of the Pot1 pathway. Mol Cell, 36(2), 193-206 (2009)
doi:10.1016/j.molcel.2009.08.009
PMid:19854130
151. Y. V. Surovtseva, D. Churikov, K. A. Boltz, X. Song, J. C. Lamb, R. Warrington, K. Leehy, M. Heacock, C. M. Price and D. E. Shippen: Conserved telomere maintenance component 1 interacts with STN1 and maintains chromosome ends in higher eukaryotes. Mol Cell, 36(2), 207-18 (2009)
doi:10.1016/j.molcel.2009.09.017
PMid:19854131
152. J. Sun, E. Y. Yu, Y. Yang, L. A. Confer, S. H. Sun, K. Wan, N. F. Lue and M. Lei: Stn1-Ten1 is an Rpa2-Rpa3-like complex at telomeres. Genes Dev, 23(24), 2900-14 (2009)
doi:10.1101/gad.1851909
153. A. D. Gelinas, M. Paschini, F. E. Reyes, A. Heroux, R. T. Batey, V. Lundblad and D. S. Wuttke: Telomere capping proteins are structurally related to RPA with an additional telomere-specific domain. Proc Natl Acad Sci U S A, 106(46), 19298-303 (2009)
doi:10.1073/pnas.0909203106
PMid:19884503
154. M. Wan, J. Qin, Z. Songyang and D. Liu: OB fold-containing protein 1 (OBFC1), a human homolog of yeast Stn1, associates with TPP1 and is implicated in telomere length regulation. J Biol Chem, 284(39), 26725-31 (2009)
doi:10.1074/jbc.M109.021105
PMid:19648609
155. F. Dantzer, M. J. Giraud-Panis, I. Jaco, J. C. Ame, I. Schultz, M. Blasco, C. E. Koering, E. Gilson, J. Menissier-de Murcia, G. de Murcia and V. Schreiber: Functional interaction between poly(ADP-Ribose) polymerase 2 (PARP-2) and TRF2: PARP activity negatively regulates TRF2. Mol Cell Biol, 24(4), 1595-607 (2004)
doi:10.1128/MCB.24.4.1595-1607.2004
PMid:14749375 PMCid:344168
156. M. Gomez, J. Wu, V. Schreiber, J. Dunlap, F. Dantzer, Y. Wang and Y. Liu: PARP1 Is a TRF2-associated poly(ADP-ribose)polymerase and protects eroded telomeres. Mol Biol Cell, 17(4), 1686-96 (2006)
doi:10.1091/mbc.E05-07-0672
PMid:16436506 PMCid:1415310
157. S. Smith, I. Giriat, A. Schmitt and T. de Lange: Tankyrase, a poly(ADP-ribose) polymerase at human telomeres (see comments). Science, 282(5393), 1484-7 (1998)
doi:10.1126/science.282.5393.1484
PMid:9822378
158. W. Chang, J. N. Dynek and S. Smith: TRF1 is degraded by ubiquitin-mediated proteolysis after release from telomeres. Genes Dev, 17(11), 1328-33 (2003)
doi:10.1101/gad.1077103
159. B. D. Cook, J. N. Dynek, W. Chang, G. Shostak and S. Smith: Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres. Mol Cell Biol, 22(1), 332-42 (2002)
doi:10.1128/MCB.22.1.332-342.2002
PMid:11739745 PMCid:134233
160. J. I. Sbodio, H. F. Lodish and N. W. Chi: Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase). Biochem J, 361(Pt 3), 451-9 (2002)
doi:10.1042/0264-6021:3610451
PMid:11802774 PMCid:1222327
161. S. Beneke, O. Cohausz, M. Malanga, P. Boukamp, F. Althaus and A. Burkle: Rapid regulation of telomere length is mediated by poly(ADP-ribose) polymerase-1. Nucleic Acids Res, 36(19), 6309-17 (2008)
doi:10.1093/nar/gkn615
PMid:18835851 PMCid:2577345
162. D. D'Amours and S. P. Jackson: The Mre11 complex: at the crossroads of dna repair and checkpoint signalling. Nat Rev Mol Cell Biol, 3(5), 317-27 (2002)
doi:10.1038/nrm805
PMid:11988766
163. T. T. Paull and M. Gellert: Nbs1 potentiates ATP-driven DNA unwinding and endonuclease cleavage by the Mre11/Rad50 complex. Genes Dev, 13(10), 1276-88 (1999)
doi:10.1101/gad.13.10.1276
164. V. Ranganathan, W. F. Heine, D. N. Ciccone, K. L. Rudolph, X. Wu, S. Chang, H. Hai, I. M. Ahearn, D. M. Livingston, I. Resnick, F. Rosen, E. Seemanova, P. Jarolim, R. A. DePinho and D. T. Weaver: Rescue of a telomere length defect of Nijmegen breakage syndrome cells requires NBS and telomerase catalytic subunit. Curr Biol, 11(12), 962-6 (2001)
doi:10.1016/S0960-9822(01)00267-6
165. Y. Bai and J. P. Murnane: Telomere instability in a human tumor cell line expressing NBS1 with mutations at sites phosphorylated by ATM. Mol Cancer Res, 1(14), 1058-69 (2003)
PMid:14707289
166. X. D. Zhu, B. Kuster, M. Mann, J. H. Petrini and T. de Lange: Cell-cycle-regulated association of RAD50/MRE11/NBS1 with TRF2 and human telomeres. Nat Genet, 25(3), 347-52 (2000)
doi:10.1038/77139
PMid:10888888
167. N. Dimitrova and T. de Lange: Cell cycle-dependent role of MRN at dysfunctional telomeres: ATM signaling-dependent induction of nonhomologous end joining (NHEJ) in G1 and resection-mediated inhibition of NHEJ in G2. Mol Cell Biol, 29(20), 5552-63 (2009)
doi:10.1128/MCB.00476-09
PMid:19667071 PMCid:2756883
168. W. Chai, A. J. Sfeir, H. Hoshiyama, J. W. Shay and W. E. Wright: The involvement of the Mre11/Rad50/Nbs1 complex in the generation of G-overhangs at human telomeres. EMBO Rep, 7(2), 225-30 (2006)
doi:10.1038/sj.embor.7400600
PMid:16374507 PMCid:1369251
169. J. H. Lee and T. T. Paull: ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science, 308(5721), 551-4 (2005)
doi:10.1126/science.1108297
PMid:15790808
170. D. Hockemeyer, A. J. Sfeir, J. W. Shay, W. E. Wright and T. de Lange: POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. Embo J, 24(14), 2667-78 (2005)
doi:10.1038/sj.emboj.7600733
PMid:15973431 PMCid:1176460
171. H. Takai, A. Smogorzewska and T. de Lange: DNA damage foci at dysfunctional telomeres. Curr Biol, 13(17), 1549-56 (2003)
doi:10.1016/S0960-9822(03)00542-6
172. Y. Deng, X. Guo, D. O. Ferguson and S. Chang: Multiple roles for MRE11 at uncapped telomeres. Nature, 460(7257), 914-8 (2009)
doi:10.1038/nature08196
PMid:19633651 PMCid:2760383
173. J. Buis, Y. Wu, Y. Deng, J. Leddon, G. Westfield, M. Eckersdorff, J. M. Sekiguchi, S. Chang and D. O. Ferguson: Mre11 nuclease activity has essential roles in DNA repair and genomic stability distinct from ATM activation. Cell, 135(1), 85-96 (2008)
doi:10.1016/j.cell.2008.08.015
PMid:18854157 PMCid:2645868
174. S. J. Collis, T. L. DeWeese, P. A. Jeggo and A. R. Parker: The life and death of DNA-PK. Oncogene, 24(6), 949-61 (2005)
doi:10.1038/sj.onc.1208332
PMid:15592499
175. L. Driller, R. J. Wellinger, M. Larrivee, E. Kremmer, S. Jaklin and H. M. Feldmann: A short C-terminal domain of Yku70p is essential for telomere maintenance. J Biol Chem, 275(32), 24921-7 (2000)
doi:10.1074/jbc.M002588200
PMid:10818099
176. H. L. Hsu, D. Gilley, S. A. Galande, M. P. Hande, B. Allen, S. H. Kim, G. C. Li, J. Campisi, T. Kohwi-Shigematsu and D. J. Chen: Ku acts in a unique way at the mammalian telomere to prevent end joining. Genes Dev, 14(22), 2807-12 (2000)
doi:10.1101/gad.844000
177. K. Song, D. Jung, Y. Jung, S. G. Lee and I. Lee: Interaction of human Ku70 with TRF2. FEBS Lett, 481(1), 81-5 (2000)
doi:10.1016/S0014-5793(00)01958-X
178. W. Chai, L. P. Ford, L. Lenertz, W. E. Wright and J. W. Shay: Human Ku70/80 associates physically with telomerase through interaction with hTERT. J Biol Chem, 277(49), 47242-7 (2002)
doi:10.1074/jbc.M208542200
PMid:12377759
179. E. Samper, F. A. Goytisolo, P. Slijepcevic, P. P. van Buul and M. A. Blasco: Mammalian Ku86 protein prevents telomeric fusions independently of the length of TTAGGG repeats and the G-strand overhang. EMBO Rep, 1(3), 244-52 (2000)
doi:10.1093/embo-reports/kvd051
PMid:11256607 PMCid:1083725
180. G. B. Celli, E. L. Denchi and T. de Lange: Ku70 stimulates fusion of dysfunctional telomeres yet protects chromosome ends from homologous recombination. Nat Cell Biol, 8(8), 885-90 (2006)
doi:10.1038/ncb1444
PMid:16845382
181. M. Tarsounas, P. Munoz, A. Claas, P. G. Smiraldo, D. L. Pittman, M. A. Blasco and S. C. West: Telomere maintenance requires the RAD51D recombination/repair protein. Cell, 117(3), 337-47 (2004)
doi:10.1016/S0092-8674(04)00337-X
182. C. Lenain, S. Bauwens, S. Amiard, M. Brunori, M. J. Giraud-Panis and E. Gilson: The Apollo 5' exonuclease functions together with TRF2 to protect telomeres from DNA repair. Curr Biol, 16(13), 1303-10 (2006)
doi:10.1016/j.cub.2006.05.021
PMid:16730175
183. M. van Overbeek and T. de Lange: Apollo, an Artemis-related nuclease, interacts with TRF2 and protects human telomeres in S phase. Curr Biol, 16(13), 1295-302 (2006)
doi:10.1016/j.cub.2006.05.022
PMid:16730176
184. V. Yankiwski, R. A. Marciniak, L. Guarente and N. F. Neff: Nuclear structure in normal and Bloom syndrome cells. Proc Natl Acad Sci U S A, 97(10), 5214-9 (2000)
doi:10.1073/pnas.090525897
PMid:10779560
185. Q. Zhu, L. Meng, J. K. Hsu, T. Lin, J. Teishima and R. Y. Tsai: GNL3L stabilizes the TRF1 complex and promotes mitotic transition. J Cell Biol, 185(5), 827-39 (2009)
doi:10.1083/jcb.200812121
PMid:19487455 PMCid:2711588
186. P. L. Opresko, C. von Kobbe, J. P. Laine, J. Harrigan, I. D. Hickson and V. A. Bohr: Telomere-binding protein TRF2 binds to and stimulates the Werner and Bloom syndrome helicases. J Biol Chem, 277(43), 41110-9 (2002)
doi:10.1074/jbc.M205396200
PMid:12181313
187. D. J. Stavropoulos, P. S. Bradshaw, X. Li, I. Pasic, K. Truong, M. Ikura, M. Ungrin and M. S. Meyn: The Bloom syndrome helicase BLM interacts with TRF2 in ALT cells and promotes telomeric DNA synthesis. Hum Mol Genet, 11(25), 3135-44 (2002)
doi:10.1093/hmg/11.25.3135
PMid:12444098
188. K. Lillard-Wetherell, A. Machwe, G. T. Langland, K. A. Combs, G. K. Behbehani, S. A. Schonberg, J. German, J. J. Turchi, D. K. Orren and J. Groden: Association and regulation of the BLM helicase by the telomere proteins TRF1 and TRF2. Hum Mol Genet, 13(17), 1919-32 (2004)
doi:10.1093/hmg/ddh193
PMid:15229185
189. L. Crabbe, R. E. Verdun, C. I. Haggblom and J. Karlseder: Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science, 306(5703), 1951-3 (2004)
doi:10.1126/science.1103619
PMid:15591207
190. B. Li, S. P. Jog, S. Reddy and L. Comai: WRN controls formation of extrachromosomal telomeric circles and is required for TRF2DeltaB-mediated telomere shortening. Mol Cell Biol, 28(6), 1892-904 (2008)
doi:10.1128/MCB.01364-07
PMid:18212065 PMCid:2268394
191. Y. Wu, T. R. Mitchell and X. D. Zhu: Human XPF controls TRF2 and telomere length maintenance through distinctive mechanisms. Mech Ageing Dev, 129(10), 602-10 (2008)
doi:10.1016/j.mad.2008.08.004
PMid:18812185
192. Y. Wu, N. J. Zacal, A. J. Rainbow and X. D. Zhu: XPF with mutations in its conserved nuclease domain is defective in DNA repair but functions in TRF2-mediated telomere shortening. DNA Repair (Amst), 6(2), 157-66 (2007)
doi:10.1016/j.dnarep.2006.09.005
PMid:17055345
193. X. D. Zhu, L. Niedernhofer, B. Kuster, M. Mann, J. H. Hoeijmakers and T. de Lange: ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol Cell, 12(6), 1489-98 (2003)
doi:10.1016/S1097-2765(03)00478-7
194. Q. Yang, Y. L. Zheng and C. C. Harris: POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol, 25(3), 1070-80 (2005)
doi:10.1128/MCB.25.3.1070-1080.2005
PMid:15657433 PMCid:544002
195. E. L. Denchi and T. de Lange: Protection of telomeres through independent control of ATM and ATR by TRF2 and POT1. Nature, 448(7157), 1068-71 (2007)
doi:10.1038/nature06065
PMid:17687332
196. C. Kelleher, I. Kurth and J. Lingner: Human protection of telomeres 1 (POT1) is a negative regulator of telomerase activity in vitro. Mol Cell Biol, 25(2), 808-18 (2005)
doi:10.1128/MCB.25.2.808-818.2005
PMid:15632080 PMCid:543404
197. M. Lei, A. J. Zaug, E. R. Podell and T. R. Cech: Switching human telomerase on and off with hPOT1 protein in vitro. J Biol Chem, 280(21), 20449-56 (2005)
doi:10.1074/jbc.M502212200
PMid:15792951
198. T. Else, A. Trovato, A. C. Kim, Y. Wu, D. O. Ferguson, R. D. Kuick, P. C. Lucas and G. D. Hammer: Genetic p53 Deficiency Partially Rescues the Adrenocortical Dysplasia Phenotype at the Expense of Increased Tumorigenesis. Cancer Cell, 15(6), 465-476 (2009)
doi:10.1016/j.ccr.2009.04.011
PMid:19477426
199. L. F. Batista and S. E. Artandi: Telomere uncapping, chromosomes, and carcinomas. Cancer Cell, 15(6), 455-7 (2009)
doi:10.1016/j.ccr.2009.05.006
PMid:19477422
200. B. Zhang, Y. X. Bai, H. H. Ma, F. Feng, R. Jin, Z. L. Wang, J. Lin, S. P. Sun, P. Yang, X. X. Wang, P. T. Huang, C. F. Huang, Y. Peng, Y. C. Chen, H. F. Kung and J. J. Huang: Silencing PinX1 compromises telomere length maintenance as well as tumorigenicity in telomerase-positive human cancer cells. Cancer Res, 69(1), 75-83 (2009)
doi:10.1158/0008-5472.CAN-08-1393
PMid:19117989
201. X. Z. Zhou and K. P. Lu: The Pin2/TRF1-Interacting Protein PinX1 Is a Potent Telomerase Inhibitor. Cell, 107(3), 347-59 (2001)
doi:10.1016/S0092-8674(01)00538-4
202. B. Guglielmi and M. Werner: The yeast homolog of human PinX1 is involved in rRNA and small nucleolar RNA maturation, not in telomere elongation inhibition. J Biol Chem, 277(38), 35712-9 (2002)
doi:10.1074/jbc.M205526200
PMid:12107183
203. M. T. Teixeira, M. Arneric, P. Sperisen and J. Lingner: Telomere length homeostasis is achieved via a switch between telomerase-extendible and -nonextendible states. Cell, 117(3), 323-335 (2004)
doi:10.1016/S0092-8674(04)00334-4
204. D. C. DeZwaan, O. A. Toogun, F. J. Echtenkamp and B. C. Freeman: The Hsp82 molecular chaperone promotes a switch between unextendable and extendable telomere states. Nat Struct Mol Biol, 16(7), 711-6 (2009)
doi:10.1038/nsmb.1616
205. S.-F. Tseng, J.-J. Lin and S.-C. Teng: The telomerase-recruitment domain of the telomere binding protein Cdc13 is regulated by Mec1p/Tel1p-dependent phosphorylation. Nucl. Acids Res., 34(21), 6327-6336 (2006)
doi:10.1093/nar/gkl786
PMid:17108359 PMCid:1669766
206. S. Li, S. Makovets, T. Matsuguchi, J. D. Blethrow, K. M. Shokat and E. H. Blackburn: Cdk1-dependent phosphorylation of Cdc13 coordinates telomere elongation during cell-cycle progression. Cell, 136(1), 50-61 (2009)
doi:10.1016/j.cell.2008.11.027
PMid:19135888 PMCid:2642970
207. S. F. Tseng, Z. J. Shen, H. J. Tsai, Y. H. Lin and S. C. Teng: Rapid Cdc13 turnover and telomere length homeostasis are controlled by Cdk1-mediated phosphorylation of Cdc13. Nucleic Acids Res (2009)
208. D. C. Zappulla, J. N. Roberts, K. J. Goodrich, T. R. Cech and D. S. Wuttke: Inhibition of yeast telomerase action by the telomeric ssDNA-binding protein, Cdc13p. Nucleic Acids Res, 37(2), 354-67 (2009)
doi:10.1093/nar/gkn830
PMid:19043074 PMCid:2632905
209. A. Puglisi, A. Bianchi, L. Lemmens, P. Damay and D. Shore: Distinct roles for yeast Stn1 in telomere capping and telomerase inhibition. EMBO J, 27(17), 2328-39 (2008)
doi:10.1038/emboj.2008.158
PMCid:2529371
210. H. Qi and V. A. Zakian: The Saccharomyces telomere-binding protein Cdc13p interacts with both the catalytic subunit of DNA polymerase alpha and the telomerase-associated est1 protein. Genes Dev, 14(14), 1777-88 (2000)
PMid:10898792 PMCid:316788
211. S. Espejel, S. Franco, A. Sgura, D. Gae, S. M. Bailey, G. E. Taccioli and M. A. Blasco: Functional interaction between DNA-PKcs and telomerase in telomere length maintenance. Embo J, 21(22), 6275-87 (2002)
doi:10.1093/emboj/cdf593
PMid:12426399 PMCid:137185
212. G. E. Lee, E. Y. Yu, C. H. Cho, J. Lee, M. T. Muller and I. K. Chung: DNA-protein kinase catalytic subunit-interacting protein KIP binds telomerase by interacting with human telomerase reverse transcriptase. J Biol Chem, 279(33), 34750-5 (2004)
doi:10.1074/jbc.M401843200
PMid:15190070
213. N. S. Ting, B. Pohorelic, Y. Yu, S. P. Lees-Miller and T. L. Beattie: The human telomerase RNA component, hTR, activates the DNA-dependent protein kinase to phosphorylate heterogeneous nuclear ribonucleoprotein A1. Nucleic Acids Res, 37(18), 6105-15 (2009)
doi:10.1093/nar/gkp636
PMid:19656952 PMCid:2764450
214. H. LaBranche, S. Dupuis, Y. Ben-David, M. R. Bani, R. J. Wellinger and B. Chabot: Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase. Nat Genet, 19(2), 199-202 (1998)
doi:10.1038/575
PMid:9620782
215. S. J. Diede and D. E. Gottschling: Exonuclease activity is required for sequence addition and Cdc13p loading at a de novo telomere. Curr Biol, 11(17), 1336-40 (2001)
doi:10.1016/S0960-9822(01)00400-6
216. H. Takata, Y. Tanaka and A. Matsuura: Late S phase-specific recruitment of Mre11 complex triggers hierarchical assembly of telomere replication proteins in Saccharomyces cerevisiae. Mol Cell, 17(4), 573-83 (2005)
doi:10.1016/j.molcel.2005.01.014
PMid:15721260
217. M. Larrivee, C. LeBel and R. J. Wellinger: The generation of proper constitutive G-tails on yeast telomeres is dependent on the MRX complex. Genes Dev, 18(12), 1391-6 (2004)
doi:10.1101/gad.1199404
218. L. Subramanian, B. A. Moser and T. M. Nakamura: Recombination-based telomere maintenance is dependent on Tel1-MRN and Rap1 and inhibited by telomerase, Taz1, and Ku in fission yeast. Mol Cell Biol, 28(5), 1443-55 (2008)
doi:10.1128/MCB.01614-07
PMid:18160711 PMCid:2258766
219. Y. J. Ju, K. H. Lee, J. E. Park, Y. S. Yi, M. Y. Yun, Y. H. Ham, T. J. Kim, H. M. Choi, G. J. Han, J. H. Lee, J. Lee, J. S. Han, K. M. Lee and G. H. Park: Decreased expression of DNA repair proteins Ku70 and Mre11 is associated with aging and may contribute to the cellular senescence. Exp Mol Med, 38(6), 686-93 (2006)
PMid:17202845
220. A. Chebel, S. Bauwens, L. M. Gerland, A. Belleville, I. Urbanowicz, A. R. de Climens, Y. Tourneur, W. W. Chien, R. Catallo, G. Salles, E. Gilson and M. Ffrench: Telomere uncapping during in vitro T-lymphocyte senescence. Aging Cell, 8(1), 52-64 (2009)
doi:10.1111/j.1474-9726.2008.00448.x
PMid:19077045
221. D. Fu and K. Collins: Purification of human telomerase complexes identifies factors involved in telomerase biogenesis and telomere length regulation. Mol Cell, 28(5), 773-85 (2007)
doi:10.1016/j.molcel.2007.09.023
PMid:18082603
222. B. van Steensel and T. de Lange: Control of telomere length by the human telomeric protein TRF1. Nature, 385(6618), 740-3 (1997)
doi:10.1038/385740a0
PMid:9034193
223. T. Bilaud, C. Brun, K. Ancelin, C. E. Koering, T. Laroche and E. Gilson: Telomeric localization of TRF2, a novel human telobox protein. Nat Genet, 17(2), 236-9 (1997)
doi:10.1038/ng1097-236
PMid:9326951
Abbreviations: DNA-PK, DNA-dependent protein kinase; MRN, MRE11, RAD50 and NBS1; TER, telomerase RNA component; TERT, telomerase reverse transcriptase
Key Words: Telomere, Telomerase, Shelterin, CST, DNA-PK, MRN, Telomere Binding Protein, Review
Send correspondence to: Jun-Ping Liu, Department of Immunology, Central Clinical School, Monash University, Alfred Medical Research and Education Precinct (AMREP), Commercial Road, Melbourne, Victoria 3004, Australia, Tel: 61-3-9594-7170, Fax: 61-3-9594-7252, E-mail:jun-ping.liu@med.monash.edu.au